Process for the preparation of ethers



United States Patent 3,151,117 PRUCESS F6 3 THE H REPARATIUN @F ETHERS Michael Mullen Robison, Berkeley Heights, and Robert Armistead Lucas, Mendham, Nil, assignors to iha Corporation, a corporation of Delaware No Drawing, Filed Apr. 23, 15363, Ser. No. 274,917 '7 Claims. (-Ql. Mil-28?) The present invention concerns 3-epi-allo-yohimbane compounds having the nucleus of the formula:

More particularly, it relates to l8-etherified hydroxy-3- epi-allo-yohimbane lofi-carboxylic acid esters, particularly l8-etherified hydroxy-l7a-R-3-epi-allo-yohimbane 1618- carboxylic acid esters, in which R represents primarily lower alkoxy, as well as cyano, salts, N-oxides or salts of N-oxicles of such compounds. Apart from the groups attached to the lo-position, the l7-position and the l8-position, the compounds of the present invention may contain additional substituents. Thus, substituents attached to the positions of the aromatic nucleus, i.e. ring A, of the molecule, more specifically to the 9-position, the lO-position, the ll-position and/or the 12-position, are represented, for example, by aliphatic hydrocarbon, such as lower alkyl and the like, etheritied hydroxyl, particularly lower alkoxy, as well as cycloalkyloxy, cycloalkyl-lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkox'y, lower alkylenedioxy and the like, esterified hydroxyl, particularly halogeno, as well as lower alkoxy-carbonyloxy, lower. alkanoyloxy and the like, etherlfied mercapto, such as lower alkylrnercapto and the like, nitro, amino, such as N,N-disubsitutecl amino and the like, substituted aliphatic hydrocarbon, such as substituted lower alkyl, for example, halogen-lower alkyl, particularly trifluoromethyl, or any other suitable substituent. Other substituents, particularly aliphatic hydrocarbon radicals, such as lower alkyl, may also be attached to positions of other nuclei, particularly of the heterocyclic nucleus C, more specifically to the -position and/ or the 6-position.

More especially, the invention is directed to compounds of the formula:

Bit

alkyl and the like, etherifiecl hydroxy-lower alkyl, e.g. lower alkoxy-lower alkyl and the like, tertiary aminoice lower alkyl, e.g. N,N-di-lower alkyl-amino-lower alkyl and the like, R stands primarily for lower alkoxy, as well as for cyano, R represents an aliphatic radical, primarily lower alkyl, as well as lower alkenyl, lower alkynyl and the like, including a cycloaliphatic radical, such as cycloalkyl or cycloalkenyl, or a substituted aliphatic radical, particularly substituted lower alkyl, which is substituted, for example, by a cycloaliphatic radical, such as cycloalkyl or cycloalkenyl, carbocylic aryl, such as monocyclic carbocyclic aryl and the like, hydroxyl, etherified hydroxyl, especially lower alkoxy and the like, esterified hydroxyl, such as lower alkoxy-carbonyloxy, lower alkanoyloxy, carbocyclic arylcarbonyloxy, carbocyclic aryllower aliphatic hydrocarbon-carbonyloxy, halogen and the like, acyl, such as lower alkanoyl, carbo-lower alkoxy and the like, mercapto, etherified mercapto, such as lower alkyl-mercapto and the like, tertiary amino, for example, N,N-di-lower alkyl-arnino and the like, a heterocyclic, particularly a monocyclic heterocyclic, radical, or any other analogous group suitable for being attached to an aliphatic radical, each of the radicals R R and R stands for hydrogen, aliphatic hydrocarbon, particularly lower alkyl and the like, substituted aliphatic hydrocarbon, particularly substituted lower alkyl, such as halogeno-lower alkyl, especially trifluoromethyl, etherir'ied hydroxyl, particularly lower alkoxy, as well as cycloalkyloxy, cycloalkyl-lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy or any other analogous etherified hydroxy group, esterified hydroxyl, particularly halogeno, as well as lower alkoxy-carbonyloxy, lower alkanoyloxy and the like, etherified mercapto, particularly lower alkyl-mercapto, nitro, amino, e.g. N,N-di-substituted amino and the like, or, whenever two of the groups R R and R are attached to two adjacent positions and are taken together, for lower alkylenedioxy, and R attached to one of the positions 5 and 6, stands for hydrogen or lower alkyl, salts, N-oxides or salts of N-oxides of such compounds, as well as process for the preparation of such compounds.

he invention is also directed to compounds of the formula:

in which each of the groups R R R R R R and R7 have the previously given meaning, salts, N-oxides or salts of N-oxides thereof, as well as process for the preparation of such compounds.

The aliphatic radical of the alcohol portion of the ester grouping attached to the 16/i-position of the molecule, which, in the above formulae, is represented by the group R stands above all for lower alkyl containing from one to ten, preferably from one to four, carbon atoms; such groups are particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and the like, as well as n-pentyl, isopentyl, n-hexyl, n-heptyl and the like.

The esterifying portion of the ester grouping attached to the l6fi-position of the molecule, represented, for example, by the radical R in the above formulae, may also stand for substituted aliphatic, particularly substituted lower alkyl, radicals, such as, for example, monocyclic carbocyclic aryl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, such as phenyllower alkyl, e.g. benzyl, l-phenyl-ethyl, Z-phenylethyl and the like, or phenyl-lower alkyl, in which phenyl is substituted by lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. rnethox ethoxy and the like, halogeno, e.g. fiuoro, chloro, bromo and the like, or any other suitable substituent.

Other substituted aliphatic, particularly lower alkyl, radicals, as represented, for example, by the group R in the above formulae, are aliphatic, especially lower alkyl, radicals substituted by functional groups, such as etherified hydroxyl, particularly lower alkoxy containing preferably from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, tertiary amino, particularly N,N-di-lower alkyl-amino, in which lower alkyl contains from one to four carbon atoms, erg. N,N-dimethylarnino, N-ethyl-N-methylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N- di-isopropylamino and the like, as well as l-N,N-alkyleneimino, in which alkylene contains from four to six ring carbon atoms, e.g. l-pyrrolidino, l-piperidino, l-N,N- hexamethyleneimino and the like, l-N,N-oxa-alkyleneimino, in which oxa-alkylene contains preferably four ring carbon atoms, e.g. 4-morpholino and the like, N,N- thia-alkylene-imino, in which alkylene contains preferably four carbon atoms, e.g. l-thiamorpholino and the like, or l-N,N-aza-alkylene-imino, in which aza-alkylene contains from four to six ring carbon atoms, particularly 4- lower alkyl-l-piperazino, e.g. 4-methyl-l-piperazino, 4- ethyl-l-piperazino and the like. The aliphatic, particularly the lower alkyl, portion in an aliphatic, especially lower alkyl, radical substituted by functional groups, such as in an etherified hydroxy-lower alkyl radical, or in a tertiary amino-lower alkyl radical and the like, may be represented by a lower alkylene radical, which contains at least two, preferably from two to three, carbon atoms, separating the functional group, such as etherified hydroxyl, tertiary amino and the like, from the l6,8-carboxyl group in the molecule by at least two, preferably by from two to three, carbon atoms. Such alkylene radicals are primarily 1,2-ethylene, 1-methyl-1,2-ethylene, 2-methyl- 1,2-ethylene, 1,3-propylene, as well as 1,4-butylene and the like. Aliphatic, particularly lower alkyl radicals containing functional groups, which radicals are represented by R in the above formulae, may be primarily lower alkoxy-lower alkyl, in which lower alkyl has from two to three carbon atoms and separates the lower alkoxy group from the l6fi-carboxyl group in the molecule by at least two carbon atoms, for example, 2-lower alkoxyethyl, e.g. 2-methoxyethyl, Z-ethoxyethyl and the like, 2-1ower alkoxy-propyl, e.g. 2-methoXy-propyl and the like, 3-lower alkoxy-propyl, e.g. methoxy-propyl, 3-ethoxypropyl and the like. Other substituted aliphatic, particularly lower alkyl radicals, are, for example, N,N-di-lower alkyl-amino-lower alkyl, in which lower alkyl carrying the N,N-di-lower alkyl-amino group has from two to three carbon atoms and separates the N,N-di-lower alkyl-amino group from the lfi-carboxyl group in the molecule by at least two carbon atoms, for example, 2-N,N-dilower alkyl-ethyl, e.g. 2-N,N-dimethylaminoethyl, 2-N,N- diethylarninoethyl and the like, 2-N,N-dilower alkylamino-propyl, e.g. 2-N,N-diethylaminopropyl and the like, 3'-N,N-di-lower alkylamino-propyl, e.g. 3-N,N-dimethylaminopropyl, 3-N,N-diethylaminopropyl and the like, N,N-alkylene-imino-lower alkyl, in which lower alkyl has from two to three carbon atoms and separates the N,N-alkylene-imino group from the 16B-carboxyl group in the molecule by at least two carbon atoms, and alkylene contains from four to seven carbon atoms, such as 2-(1- N,N-alkylene-imino)-ethyl, e.g. 2-(1-pyrrolidino)-ethyl, 2-(l-piperidino)-ethyl and the like, 2-(l-N,N-alkyleneimino)-propyl, e.g. 2-(l-pyrrolidino)-propyl, 2-(l-pipercidino)-propyl and the like, 3-(l-N,N-alkylene-imino)- propyl, e.g 3-(l-pipericlino)-propyl, (3-( l-N,N-hexarnethylene-imino)-propyl and the like, or any other suitable tertiary amino-lower alkyl radical.

The substituent attached to the Hot-position, as represented by the group R in the above formulae, represents lower alkoxy which contains preferably from one to four carbon atoms, and stands primarily for methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like. It may also stand for cyano.

The etherified hydroxyl group attached to the l8-position and represented, for example, by the grouping R O in the previously given formulae, is etherified by an aliphatic radical including a cycloaliphatic or a substituted aliphatic radical. These radicals, represented in the above formulae by the group R stand, above all, for lower alkyl, containing from one to ten, preferably from one to seven, carbon atoms such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, n-pentyl, isopentyl, neopentyl, n'hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

Other etherified 18-hydroxyl groups have as the etherifying portions, represented, for example, by the radical R in the above-given formulae, other aliphatic radicals, such as, for example, lower alkenyl, particularly lower allylic alkenyl, containing preferably from three to five carbon atoms, e.g. allyl, Z-methyl-allyl, Z-butenyl, 3-methyl-2-butenyl, Z-pentenyl and the like, lower alkynyl, e.g. propargyl and the like, or cycloaliphatic radicals, such as cycloalkyl containing from three to eight, ring carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl and the like, or cycloalkenyl, containing preferably from five to eight ring carbon atoms, e.g. 3-cyclopentenyl, Z-cyclohexenyl and the like.

Aliphatic radicals etherifying the 18-hydroxyl group, as represented by R in the above formulae, may contain substituents, such as, for example, cycloaliphatic radicals. Accordingly, substituted aliphatic radicals may be represented by cycloaliphatic-aliphatic radicals, for example, by cycloalkyl-lower alkyl, in which cycloalkyl contains from three to eight ring carbon atoms, and lower alkyl contains from one to four carbon atoms, e.g. cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, l-cyclopentylethyl, 2-cyclopentylethyl, 3-cyclopentylpropyl, cyclohexylrnethyl, Z-cyclohexylethyl and the like, cycloalkyl-lower alkenyl, in which cycloalkyl has the above-given meaning, and lower alkenyl contains preferably from three to five carbon atoms, e.g. 3-cyclopropyl-allyl, 3-cyclopentyl-allyl and the like, cycloalkenyllower alkyl, in which cycloalkenyl contains from five to eight ring carbon atoms, and lower alkyl has from one to four carbon atoms, e.g. 2-(1-cyclopentenyl)-ethyl, 2- cyclohexenylmethyl, 3-cyclohexenylmethyl and the like.

Other substituted aliphatic radicals contain as substituents carbocyclic aryl groups and represent, for example, carbocyclic aryl-aliphatic radicals, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyllower alkyl, e.g. benzyl, diphenylmethyl, l-phenylethyl, 2- phenylethyl and the like, as well as carbocyclic-lower alkenyl, such as monocyclic carbocyclic aryl-lower alkenyl, particularly phenyl-lower alkenyl, e.g. 3-phenyl-allyl and the like, or analogous radicals, in which the carbocyclic aryl nucleus is substituted by one or more than one of the same or different substituents, for example, by lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. fiuoro, chloro, bromo and the like, lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, halogeno-lower alkyl, e.g. trifluorornethyl and the like, nitro, amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dirnethylamino and the like, or any other suitable substituent.

Other substituted aliphatic radicals, particularly lower alkyl groups, represented inthe above formulae by the group R may be substituted by functional groups, particularly by hydroxyl or etherified hydroxyl. Aliphatic radicals containing hydroxyl groups are, for example, hydroxy-aliphatic radicals, such as hydroxy-lower alkyl, in

which the hydroxyl group is separated from the 18-oxygen atom in the molecule by at least two carbon atoms, e.g. 2-hydroxyethyl, Z-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, S-hydroxypentyl and the like.

Etherified hydroxy-aliphatic radicals are primarily represented by lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms, and stands, for example, for methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, and in which the lower alkoxy group is separated from the Iii-oxygen atom in the molecule by at least two carbon atoms; lower alkoxylower alkyl groups be represented by 2-lower alkoxyethyl, e.g. Z-methoxyethyl, Z-ethoxyethyl, 2isopropyloxyethyl and the like, 2-lower alkoxy-propyl, e.g. Z-methoxypropyl, 2-ethoxypropyl, Z-n-propyloxypropyl and the like, 3-lower alkoxypropyl, e.g. 3-methoxypropyl, 3-ethoxypropyl and the like, or any other analogous lower alkoxylower alkyl group.

Other etherified hydroxyl groups, which may substitute aliphatic, particularly lower alkyl, radicals are, for example, lower alkenyloxy, e.g. vinyloxy, allyloxy and the like, cycloalkyloxy, in which cycloalkyl has from three to eight ring carbon atoms, e.g. cyclopentyloxy, cyclohexyloxy and the like, cycloalkenyloxy, in which cycloalkenyl has from five to eight ring carbon atoms, e.g. 3- cyclohexenyloxy and the like, cycloalkyl-lower alkoxy, in which cycloalkyl has from three to eight ring carbon atoms, e.g. cyclopentylmethyloxy, 2-cyclohexylethyloxy and the like, lower alkoXy-lower alkoxy, e.g. 2-methoxyethoxy, Z-ethoxy-ethoxy, E-methoxy-propyloxy and the like, w-lower alkoxy-alkoxy-poly-lower alkylenoxy, eg. to methoxy-diethyleneoxy, w-ethoxy-diethyleneoxy, wmethoxy-tetraethyleneoxy, w-methoxy-nonaethyleneoxy, w-methoxy-dodecaethylenoxy and the like, or any other suitably etherified hydroxyl group. Aliphatic, particularly lower alkyl, groups carrying such etherified hydroxyl groups are, for example, lower alkenyloxy-lower alkyl, in which the lower alkenyloxy group is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, for example, 2-lower alkenyloxyethyl, e.g. 2- vinyloxyethyl, 2-allyloxyethyl and the like, 2-1ower alkenyloxy-propyl, e.g. 2-vinyloxypropyl and the like, 3- lower alkenyloxy-propyl, e.g. 3-vinyloxypropyl, 3-allyloxypropyl and the like, cycloalky1oxy-lower alkyl, in which cycloalkyloxy is separated from the lS-oxygen atom in the molecule by at least two carbon atoms, such as 2- cycloakyloxy-ethyl, e.g. Z-cyclopentyloxyethyl and the like, 2-cycloalkyloxy-propyl, e.g. 2-cyclohexyloxypropyl and the like, 3-cycloalkyl-propyl, e.g. 3-cyclopentyloxypropyl and the like, cycloalkenyloxy-lower alkyl, in which cycloalkenyloxy is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, such as 2-cycloalkenyloxy-ethyl, e.g. 2-(2-cyclopentenyloxy)ethy1 and the like, 2-cycloalkenyloxy-propyl, e.g. 2-(3-cyclohexenyloxy)-propyl and the like, B-cycloalkenyloxypropyl, e.g. 3- (3-cyclopentenyloxy)-propyl and the like, cycloalkyllower alkoxy-lower alkyl, in which cycloalkyl-lower alkoxy is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, such as Z-(cycloalkyl-lower alkoxy)-ethyl, e.g. 2-cyclopentylmethyloxyethyl and the like, Z-(cycloalkyl-lower alkoxy)-propyl, e.g. 2-(2-cyclohexylethoxy)-propyl and the like, 3-cycloalkyl-lower alkoxy)-propyl, e.g. 3-cyclohexyl-methoxypropyl and the like, lower alkoxy-lower alkoxy-lower alkyl, in which lower alkoxy-lower alkoxy is separated from the lit-oxygen atom in the molecule by at least two carbon atoms, such as Z-(lower alkoxy-lower alkoxy)-ethyl, e.g. Z-(Z-methoxyethoxy) ethyl, 2- (Z-ethoxy-ethoxy) -ethyl, 2- (Z-isopropyloxyethoxy)-ethyl and the like, 2-(1ower alkoxy-lower alkoxy)-propyl, e.g. 2-(Z-methoxyethoxy)-propyl, 2-(2- ethoxyethoxy)-propyl and the like, 3-(lower alkoxy-lower alkoxy)-propyl, e.g. 3(2-methoxyethoxy)-propyl, 3-(2- ethoxyethoxy)-propyl and the like, (w-lower alkoxy-polylower alkyleneoxy)-lower alkyl, in which w-lower alkoxypoly-lower alkyleneoxy is separated from the 18-oxygen atom in the molecule by at least two carbon atoms, such as Z-(w-lower alkoxy-polydo 'er alkylencoxy)-ethyl, e.g. 2- w-methoxy-diethyleneoxy -ethyl, 2- w-ethoxy-tetraethyleneoxy)-ethyl, 2-(w-methoxy-nonaethyleneoxy) ethyl and the like, 2-(w-lower alkoxy-poly-lower alkyleneoxy)- propyl, e.g. 2-(w1nethoxy-triethyleneoxy)-propyl, Z-(wethoxy-tetraethyleneoxy) -propyl, 2- (w-methoxy-nonaethyleneoxy)-propyl and the like, 3-(w-lower alkoxy-poly-lower alkyleneoxy)-propyl, e.g. 3-(w-methoxy-diethyleneoxy -propyl, 3 e-ethoxy-tetraethyleneoxy) -propyl, 3 wmethoxy-nonaethyleneoxy)-propyl and the like, or any other analogous aliphatic group carrying an etherified hydroxyl group.

Other substituted aliphatic, especially substituted lower alkyl, radicals contain as substitutents esteriiied hydroxyl groups, such as lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoxy-carbonyloxy and the like, lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, carbocyclic aryl-carhonyloxy, particularly monocyclic carbocyclic aryl-carbonyloxy, e.g. benzoyloxy, and benzoyloxy, in which the carbocyclic aryl portion is substiutted by the same or different substituents attached to any of the positions available for substitution, such as, for example, by lower alkyl, e.g. methyl, ethyl, isopropyl and the like, lower alkoxy, e.g. methoxy, ethoxy, n-butyloxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, lower alkoxy-carboyloxy, e.g. methoxy-caroonyloxy, ethoxy-carbonyloxy and the like, polyhalogeno-lower alkyl, e.g. trifluoromethyl and the like, nitro, amino, such as N,N-di-1ower alkylamino, e.g. N,N-dimethylamino and the li re, or any other suitable substituent, carbocyclic aryl-lower aliphatic hydrocarbon-carbonyloxy, such as monocyclic carbocyclic aryl-lower alkanoyloxy or monocyclic carbocyclic aryllower alkenoyloxy, e.g. phenyl-acetoxy, 3-phenyl-propionyloxy, cinnamoyloxy and the like, and these radicals substituted in the carbocyclic nucleus by one or more than one of the same or of diflerent substituents, such as those mentioned hereinbefore, or halogeno (representing a hydroxyl group esterified with a hydro-hallo acid), e.g. fluoro and the like. Aliphatic, particularly lower alkyl, radicals substituted by esterified hydroxyl groups, in which the esteriiied hydroxyl group is separated from the 18- oxygen atom of the molecule by at least two carbon atoms, may be represented, for example, by lower alkoxy-carbom yloxy-lower alkyl, in which the esterified hydroxyl group is being separated from the l8-oxygen atom in the molecule by at least two carbon atoms, such as 2-lower alkoxy-carbonyloxy-ethyl, e.g. Z-methoxy-oarbonyloxy-ethyl and the like, 2-lower alkoxy-carbonyloxy-propyl, e.g. 2-ethoxy-carbonyloxy-propyl and the like, i -lower alkoxycarbonyloXy-propyl, e.g. 3-methoxy-carbonyloxy-propyl and the like, lower alkanoyloxy-lower alkyl, in which the esterified hydroxyl group is being separated from the 18- oxygen atom in the molecule by at least two carbon atoms, such as Z-lower alkanoyloxy-ethyl, e.g. 2-acetyloxy-ethyl, Z-propionyl-oxyethyl and the like, 2-lower alkanoyloxypropyl, e.g. Z-acetyloxy-propyl and the like, 3-lower alkanoyloxy-proyl, e.g. 3-acetyloxy-propyl and the like, monocyclic carbocyclic aryl-carbonyloxy-lower alkyl, in which the esterified hydroxyl group is being separated from the 18-oxygen atom in the molecule by at least two carbon atoms, such as 2-monocyclic carbocyclic aryl-carbonyloxy-ethyl, e.g. 2-benzoyloxyethy1, 2-(3,4,5-trimethoxy benzoyloxy)-ethyl, 2-(4-ethoxycarbonyl-syringoyloxy)-ethyl and the like, 2-monocyclie carbocyclic arylcarbonyloxy-propyl, e.g. Z-benzoyloxy-propyl and the like, 3-monocyclic carbocyclic aryl-carbonyloxy-propyl, e.g. 3- benzoyloxypropyl, 3-(3,4,S-trimethoxy-benzoyloxy)- propyl and the like, monocyclic carbocyclic aryl-lower a1- kanoyloxy-lower alkyl, in which the esterified hydroxyl group is separated from the lS-oxygen atom in the molecule by at least two carbon atoms, such as 2-monocyclic carbocyclic aryl-lower alkanoyloxy-ethyl, e.g. 2-[3-(3,4,5- trimethoxy-phenyl)-propionyloxy]-ethyl and the like, 2- monocyclic carbocyclic aryl-lower alkanoyloxy-propyl, e.g. Z-phenylacetyloxypropyl and the like, B-monocyclic carbocyclic aryl-lower alkanoyloxy-propyl, e.g. S-phenylacetyloxypropyl and the like, monocyclic carbocyclic aryl-lower alkenoyloxy-lower alkyl, in which the esterified hydroxyl group is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, such as 2- (monocyclic carbocyclic aryl-lower alkanyloxy)-ethyl, e.g. Z-cinnamoyloxyethyl and the like, Z-mOno-cyclic carbocyclic aryl-lower alkenoyloxy-propyl, e.g. Z-cinnarnoyloxy-propyl and the like, S-(monocyclic carbocyclic aryllower alkenoyloxy)-propyl, e.g. 3-(3,4,5-trimethoxy-cinnarnoyloxy)-propyl and the like, halogeno-lower alkyl, in which halogeno is separated from the lS-oxygen atom in the molecule by at least two carbon atoms such as, for example, Z-trifluoroethyl and the like.

Other aliphatic, particularly lower alkyl, radicals etheritying the l8-hydroxyl group and represented, for exam ple, by R in the above formulae, may be substituted by acyl, particularly lower alkanoyl, e.g. acetyl, propionyl and the like, or carbo-lower alkoxy, e.g. carbomethoxy, carbethoxy and the like; such aliphatic radicals may be represented, for example, by lower alkanoyl-lower alkyl, e.g. acetonyl, butan-Z-onyl, butan-3-onyl and the like, carbo-lower alkoxy-lower alkyl, e.g. carbornethoxy-methyl-2-carbethoxyethyl and the like.

Additional aliphatic, particularly lower alkyl, radicals etherifying the lS-hydroxyl group and represented, for example, by R in the above formulae, may be substituted by mercapto or etherifie-d mercapto, such as lower alkylmercapto, e.g. rnethyl-mercapto, ethylrnercapto and the like, and represent mercapto-lower alkyl, in which the mercapto group is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, e.g. 2-mercaptoethyl, Z-mercaptopropyl, B-mercaptopropyl and the like, or lower alkyl-mercapto-lower alkyl, in which lower alkyl-rnercapto is separated from the l8-oxygen atom in the molecule by at least two carbon atoms, such as 2 lower alkylmercaptoethyl, e.g. Z-methylmercaptoethyl, lethylmercaptoethyl and the like, 2-lower alkyl-mercaptopropyl, e.g. Z-methylmercaptopropyl and the like, 3-lower alkyl-mercapto-propyl, e.g. 3-ethylmercaptopropyl and the like.

Still other aliphatic, particularly lower alkyl, radicals etherifying the 18-hydroxy1 group and represented, for example, by the group R in the above formulae, may be substituted by amino, particularly tertiary amino, such as N,N,-di-lower alkylamino, eg. N,N-dimethylamino, N- ethyl-N-methyl-amino, N,N-diethylamino, Ndl-di-n-propylamino, N,Ndi-isopropylarnino, ILN-dibutylamino and the like, N,N-alkylene-imino, in which alkylene contains from four to seven carbon atoms, e.g. l-pyrrolidino, 1- piperidino, l-N,N-hexamethyleneimino and the like, N, N-oxaalkylene-irnino, in which alkylene contains primarily four carbon atoms, e.g. 4-morpholino and the like, N,N-thia-alkylene-imino, in which alkylene has primarily four carbon atoms, e.g. l-thiamorpholino and the like, lLN-aza-alkylene-imino, in which alkylene contains from four to six ring carbon atoms, particularly 4-lower alkyl-l-piperazino, e.g. 4-methyl-l-piperazino, 4-ethyl-lpiperazino and the like. Aliphatic radicals substituted by a tertiary amino group are primarily tertiary amino-lower alkyl, such as N,N-di-lower alkyl-amino-lower alkyl, in which lower alkyl carrying the N,N-di-lower alkyl-amiuo group has from two to three carbon atoms and separates the tertiary amino group from the l8-oxygen atom in the molecule by at least two carbon atoms, for example, 2- N,N-di-lower alkylamino-ethyl, eg. 2-N,N-dimethylarninoethyl, 2-l-l,N-diethylaminoethyl and the like, Z-N, N-di-lower alkyl-amino-propyl, e.g. 2-N,N-dimethylaminopropyl, 2-N,N-diethylaminopropyl and the like, 3-N, N-di-lower alkyl-amino-propyl, e.g. 3-N,N-dimethylaminopropyl, 3-N,N-diethylaminopropyl and the like, l-N,N- alkylene-imino-lower alkyl, in which lower alkyl has from two to three carbon atoms and separates the N,Nalkylene-imino group from the l8-oxygen atom in the molecule by at least two carbon atoms, and alkylene contains from four to seven carbon atoms, for example, 2-N-N-alkyleneiminoethyl, e.g. 2-(l-pyrrolidino)-ethyl, 2-(l-piperidino)- ethyl and the like, 2-N,N-alkylene-irnino-propyl, e.g. 2- (l-pyrrolidino)-propyl, and the like, 3-N,N-alkyleneimino-propyl, e.g. 3-(l-piperidino)-propyl and the like, 4-morpholino-lower alkyl, in which lower alkyl has from two to three carbon atoms and separates the morpholino group from the lit-oxygen atom in the molecule by at least two carbon atoms, such as 2-(4-morpholino)-ethyl, 2 4-morpholino -propyl, 3 (4-morpholino -propyl, and the like, 4-lower alkyl-l-piperazino)-lower alkyl, in which lower alkyl, carrying the 4-lower alkyl-l-piperazino group, has from two to three carbon atoms and separates the 4-lower alkyl-l-piperazino group from the 18-oxygen atom in the molecule by at least two carbon atoms, for example, 2-(4-lower alkyl-l-piperazino)ethyl, e.g. 2-(4- methyll-piperazino -ethyl, 2- (4-ethyll-piperazino -ethyl and the like, 2-(4-lower alkyl-l-piperazino)-propyl, e.g. 2-(4-ethyl-l-piperazino)-propyl and the like, 34-lower aikyl l piperazino) propyl, e.g. 3 (4-methyi-l-pipera- Zino -propyl, 3- 4-ethyll -piperazino -propyl and the like, as well as other analogous aliphatic radicals substituted by tertiary amino groups.

Aliphatic, particularly lower alkyl, radicals may also contain heterocyclic groups as substituents, which are attached to the aliphatic, e.g. lower alkyl, radical through one of their ring carbon atoms. Such groups are, for example, monocyclic heterocyclic aryl groups, especially monocyclic azacyclic aryl groups, such as pyridyl, e.g. 2- pyridyl, 4-pyridyl and the like, thienyl, e.g. Z-thienyl and the like or monocyclic cyclohetero-aliphatic groups, such as tetrahydrofuranyl, e.g. Z-tetrahydrofuranyl and the like. Aliphatic radicals substituted by a heterocyclic radical may be represented, for example, by pyridyl-lower alkyl, e.g. Z-pyridylmethyl, 2-(4-pyridyl)-ethyl, and the like, thienyl-lower alkyl, e.g. Z-thenyl and the like, tetrahydroiuranyl-lower alkyl, e.g. 2-tetrahydrofuranylmcthyl and the like.

Substituents attached to any or" the positions available for substitution in ring A, particularly those represented by the groups R R and R (each of which may also stand for hydrogen) in the previously given formulae, may be, for example, lower aliphatic hydrocarbon, especially lower alkyl, containing preferably from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl and the like, or functional groups, such as, for example, etherified hydroxyl, particularly lower alkoxy, containing prefer-ably from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isorbutyloxy, secondary butyloxy, tertiary butyloxy and the like, as well as lower alkenyloxy, e.g. allyloxy and the like, cycloalkyloxy, in which cycloalkyl contains from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentyloxy, cyclohexyloxy and the like, cycloalkyl-lower alkoxy, in which cycloalkyl contains from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentylmethoxy, Z-cyclopentylethoxy, cyclohexylmethoxy and the like, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, cg. phenyloxy and the like, carbocyclic aryl-lower alkoxy, such as monocyclic carbocyclic aryl-lower alkoxy, for example, phenyl-lower alkoxy, e.g. benzyloxy, diphenylmethoxy, 2-phenylethoxy and the like, esterified hydroxyl, particularly halogeno (representing hydroxyl esterified by a hydrohalic acid), particularly halogeno having an atomic Weight of 19 to 80, 6g. fiuoro, chloro, bromo and the like, lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and the like, or lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, etherified mercapto, particularly lower alkylmercapto, containing preferably from one to four carbon atoms, e.g. methylmercapto ethylmercapto and the like, nitro, amino, particularly N,N-di-substituted amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino,

N-ethyl-N-methyl-amino, N,N-diethylamino and the like, polyhalogeno-lower alkyl, particularly tn'fiucromethyl and the like, or any other suitable functional group. A substituent may also be attached to two adjacent positions of ring A and form a ring fused onto the Aring; for example, two of the radicals R R and R in the formulae, when substituting two neighboring positions and taken together, may also form a fused-on cyclic substituent. Such substituents may be represented, for example, by lower alkylene-dioxy, e.g. methylenedioxy, 1,1-ethylenedioxy and the like, or any other analogous grouping.

Substituents, which may be attached to other positions in the molecule, particularly to positions in ring C, which are available for substitution, are primarily aliphatic hydrocarbon, such as lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl and the like. The radical R in the previously given formulae, which stands primarily for hydrogen, may, therefore, also represent lower alkyl, particularly methyl, as Well as ethyl and the like.

Salts of the compounds of this invention are primarily therapeutically and pharmacologically acceptable, nontoxic acid addition salts, particularly those with inorganic acids, such as mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, as Well as with organic acids, e.g. acetic, maleic, citric, tartaric, methane sulfonic, ethane sulfonic, 1,2-ethane disulfonic, p-toluene sulfonic acid and the like.

Also included within the scope of the present invention are the N-oxides of the above-described compounds, as well as the pharmacological-1y acceptable acid addition salts of these N-oxides, such as the addition salts with the above-mentioned inorganic, particularly mineral, and organic acids.

In view of the fact that several asymmetric carbon atoms are present in the compounds of this invention, the latter may be obtained in the form of a mixture of racem-ates, racemates or optically pure compounds.

The compounds of the present invention exhibit pharmacological properties and can be used accordingly. In contrast to the naturally occurring Rauwolfia diester alkaloids, the compounds of this invention react rapidly, the pharmacological action is of definite duration and the recovery from the effects is complete; in other words, the compounds of this invention can be used in cases of emergency, and their actions are easily controllable. Furthermore, the non-toxic acid addition salts of these compounds are to a high degree water-soluble, and are, therefore, extremely useful in the preparation of pharm-aceutical compositions, particularly of aqueous solutions for injection and aqueous oral preparations, e.g. elixirs and the like.

The compounds of this invention exhibit sedative and tranquilizing properties, as well as antihypertensive, antifibrillatory and/or local anesthetic eifects. The degree of and the ratio between each of these properties may vary considerably. Thus, some of the compounds of this invention show strong sedative and tranquilizing effects with negligible antihypertensive or antifibrillatory properties, whereas in others, these predominant sedative and tranquilizing activities are accompanied by beneficial antifibrillatory effects. Again others exhibit pronounced antihypertensive properties, while the sedative and tranquilizing components are much weaker. In addition to such differentiation-s in the activity pattern, certain compounds of this invention exhibit local anesthetic properties.

Depending on the predominant pharmacological effects, the compounds of the present invention can, therefore, be used as sedative and tranquilizing agents to relieve states of hyperactivity, tension and agitation, as, for example, associated with mental disturbances, anxiety and the like, as antihypertensive compounds to counteract hypertensive conditions, such as, for example, renal hypertension, toxemia and the like, in the treatment of cardiac irregularities, including extrasystoles, auricular fibrillation and the like, and/or as local anesthetics in connection With minor surgery or in the treatment of burns.

Compounds of this invention are particularly suitable in calming laboratory test animals, such as monkeys, cats, dogs and the like, prior to handling; some of the compounds can be used as local anesthetics during animal surgery performed, for example, in connection with the testing of pharmacologically acitve compounds influencing the functioning of certain organs, such as the adrenal glands, kidneys and the like.

Furthermore, compounds of this invention with sedative and tranquilizing eifects can also be used in the veterinary field to quiet animals, particularly chickens, turkeys and the like, as well as other domestic animals to facilitate handling during vaccination, shipment and the like.

A preferred group of compounds is represented by the formula:

in which each of the letters m and n represents one of the whole numbers from one to seven, particularly from one to three, and R is lower alkoxy having from one to four carbon atoms, particularly methoxy, as Well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the l0-position or the I l-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof,

These compounds are represented by the lower alkyl l8-O-lower alkyl reserpates, in which lower alkyl has from one to seven, especially from one to three, carbon atoms, or the non-toxic, pharmacologically acceptable acid addition salts thereof, particularly by the methyl l8-O-lower alkyl-reserpates, in which lower alkyl has from one to three carbon atoms and is represented by methyl, ethyl, npropyl or isopropyl, or the non-toxic, pharmacologically acceptable acid addition salts. Compounds of this type, particularly the above-mentioned methyl l8-O-lower alkyl-reserpates or the non-toxic, pharmacologically acceptable acid addition salts thereof, are characterized by predominant sedative and tranquilizing effects accompanied by negligible antihypertensive or antifibrillatory properties.

Another group of preferred compounds may be represented by the formula:

in which each of the letters m and n represents one of the whole numbers from one to seven, particularly from it It one to three, and R represents lower alkoxy having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy and the like, whereby R is preferably attached to the 10-position or the ll-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof.

These compounds are represented by the lower alkyl IS-epi-O-lower alkyl-reserpates, in which lower alkyl has from one to seven, especially from one to three carbon atoms, particularly by the methyl 18-epi-O-lower alkylreserpates, in which lower alkyl has from one to three carbon atoms and is represented by methyl, ethyl, n-propyl or isopropyl, or the non-toxic pharmacologically acceptable acid addition salts thereof. Compounds of this type, particularly the above-mentioned methyl IS-epi-O- lower alkyl-reserpates or the non-toxic, pharmacologically acceptable acid addition salts thereof, are characterized by strong sedative and tranquilizing properties which can be accompanied by anti-fibrillatory and local anesthetic effects, but shown only negligible antihypertensive activities.

Another preferred group of compounds is represented by the formula:

o a bon in which the letter 11 represents one of the whole numbers from one to seven, particularly from one to three, and the letter 2 stands for one of the whole numbers from two to seven, particularly from two to five, and in which the radical of the formula -(C H separates the two oxygen atoms attached to such radical by at least two carbon atoms, and R is lower alkoxy having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the l-position or the lit-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof.

These compounds are primarly represented by the lower alkyl lS-epi-O-(hydroxy-lower alkyl)-reserpates, in which lower alkyl of the ester group has from one to seven,

especially from one to three carbon atoms, and lower alkyl of the hydroxy-lower alkyl group has from two to seven, particularly from two to five carbon atoms separating the hydroxyl group from the IS-oxygen atom by at least two carbon atoms, or the non-toxic, pharmacologically acceptable acid addition salts thereof, particularly by the methyl 18-epi-O-(hydroxy-lower alkyl)-reserpates, in which lower alkyl has from two to five carbon atoms separating the hydroxyl group from the l8-oxygen atom by at least two carbon atoms, or the non-toxic pharmacologically acceptable acid addition salts thereof. Compounds of this type, particularly the above-mentioned methyl l8-epi-O-(hydroxy-lower alkyD-reserpates or the non-toxic, pharmacologically acceptable acid addition salts thereof, show strong sedative and tranquilizing properties, accompanied by negli ible antihypertensive effects. Another group of preferred compounds having outstanding sedative and tranquilizing properties is presented by the formula:

in which the letter in stands for one of the whole numbers from one to seven, particularly from one to three, the letter w stands for one of the whole numbers from one to four, and the letter y stands for one of the whole numbers from two to three, and in which the radical of the formula (C H separates the two oxygen atoms attached to such radical by at least two carbon atoms, and R represents lower alkoxy having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the IO-position or the ll-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof.

Compounds of the above type are primarily the lower alkoxy-lower alkyl IS-epi-O-lower alkyl-reserpates, in which lower alkyl substituting the lit-oxygen atom has from one to seven, especially from one to three carbon atoms, and lower allcyl of the lower alkoXy-lower alkyl group has from two to three carbon atoms, which separate the lower alkoxy group having from one to four carbon atoms, by at least two carbon atoms from the 16,8-carboxyl group, or the non-toxic, pharmacologically acceptable acid addition salts thereof. Compounds of this type, particularly the above-mentioned lower alkoxylower alkyl 18-epi-O-lower alkyl-reseipates or the nontoxic, pharmacologically acceptable acid addition salts thereof, are characterized by strong sedative and tranquilizing effects and show only negligible antihypertensive properties.

A further group of preferred compounds is represented by those having the formula:

in which each of the letters w and x stands for one of the whole numbers from one to four, and each of the letters y and z stands for one of the whole numbers from two to three, and each of the radicals of the formulae (C l-l and (C H separates the two oxygen atoms attached to such radicals by at least two carbon atoms, and R is lower alkoxy having from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, ispropyloxy, n-butyloxy and the like, whereby R is preferably attached to the l0-positi'on or the ll-position, or the non-toxic, pharmacologically acceptable acid addition salts thereof.

Compounds of the above type are primarily the lower alkoxy-lower alkyl 18-epi-O-(lower alkoxy-lower alkyl)- reserpates, in which lower alkyl has from two to three carbon atoms, which separate the lower alkoxy group, having from one to four carbon atoms, by at least two carbon atoms from the l6,B-carboxyl group and the l8 oxygen atom, respectively, or the non-toxic, pharmacologically acceptable acid addition salts thereof. Compounds of this type, particularly the above-mentioned lower alkoxy-lower alkyl 18 epi O lower alkoxy-lower alkyl-reserpates or pharmacologically acceptable acid addition salts thereof, have antihypertensive properties accompanied by less pronounced and negligible sedative and tranquilizing effects.

The compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new compounds or derivatives thereof, such as nontoxic, pharmacologically acceptable acid addition salts, N-oxides or pharmacologically acceptable acid addition salts of N-oxides thereof, in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed inert substances, which are compatible with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known inert carrier used in pharmaceutical preparations. These may be in solid form, for example, as tablets capsules dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain additional substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers or any other auxiliary substances. They may also contain in combination, other therapeutically useful substances.

Compounds of this invention can be formed by etherifying in an 18-hydroxy-3-epi-allo-yohimbane ISfl-carboxylic acid ester, a salt, an N-oxide or a salt of an N-oxide thereof, the free hydroxyl group attached to the 18-position by treatment with a diazo-compound in the presence of a strong inorganic Lewis acid, and, if desired, converting a resulting salt into the free base, and/or, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof, and/or, if desired, converting a resulting mixture of isomers into the single isomers.

A salt of the starting material or of an N-oxide thereof, is an addition salt with an acid, primarily a salt with an inorganic, such as a mineral, acid, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like. An acid addition salt may also be a salt with the strong inorganic Lewis acid catalyzing the etherification reaction, e.g. fluoboric acid and the like; such salt may be formed during the reaction.

The starting material is reacted with the diazo com pound, particularly a lower diazo-alkane, e.g. diazomethane, diazoethane, n-diazopropane, n-diazobutane, diazoisobutane, n-diazopentane and the like, or any other suitable diazo reagent, in the presence of a strong inorganic Lewis acid. Fluoboric acid, which may be employed in the form of a concentrated aqueous solution (for example, as an about 12 N to an about 16 N aqueous solution), represents the preferred reagent. Other Lewis acid reagents may be, for example, perchloric acid (preferably in anhydrous form) and the like. Due to the salt-forming properties of free starting material, the Lewis acid, catalyzing the etherification of the ls-hydroxyl group, is used in excess of one mol, whenever the free base is present; an about one to an about two hundred, preferably an about ten to an about fifty, percent excess appears to be sufficient to promote the etherification reaction.

The reaction is carried out in the presence of an organic solvent, which is inert towards the starting material, the diazo reagent and the Lewis acid. Appropriate diluents are, for example, halogenated lower aliphatic hydrocarbons, e.g. methylene chloride, chloroform, ethylene chloride, trichloroethane, tetrachloroethane and the like, ethers, e.g. diethylether, tetrahydrofuran and the like, lower alkyl lower alkanoates, e.g. methyl acetate, ethyl acetate and the like, acetonitrile or any other useful solvent, as well as mixtures of solvents, such as those mentioned hereinabove. A solution of the diazo reagent in an inert solvent, such as an ether, e.g. diethyl ether and the like, or a halogenated hydrocarbon, e.g. methylene chloride and the like, or a mixture of solvents, may be added to the mixture of the starting material and the Lewis acid, preferably kept in solution. The diazo compound may also be distilled out of a solution into the solution of the mixture of the starting material and the Lewis acid. Furthermore, the latter mixture may also be given to a solution of the diazo reagent.

The reaction may be carried out at room temperature; however, cooling of the reaction mixture to below room temperature, for example, to from about 10 to about --20, especially to from about 0 to about 15, may be advantageous. If necessary, the reaction may be carried out in the atmosphere of an inert gas, e.g. nitrogen and the like.

An excess of the diazo reagent present at the end of the reaction may be destroyed, for example, by adding an acid, preferably an easily esterifiable organic carboxylic acid, e.g. acetic, benzoic acid and the like.

The desired product may be isolated and separated from any by-products according to standard procedures, e.g. extraction, adsorption and elution, crystallization, etc. and purified, for example, by recrystallization, if necessary, after treatment of a solution thereof with an absorbent, e.g. aluminum oxide, charcoal, diatomaceous earth and the like.

Starting materials used in the above procedure are known. Others, such as the 18ot-hydroxy 3 epi alloyohimbane lofi-carboxylic acid esters, may be prepared, for example, by reacting an lite-organic sulfonyloxy-3- epi-allo-yohimbane l6B-carboxylic acid ester, in which the organic radical represents primarily monocyclic carbocyclic aryl, such as phenyl, or substituted phenyl, a salt, an N-oxide or a salt of an N-oxide thereof, with water to form the desired l8u-hydroxy-3-epi-allo-yohim bane 16B-carboxylic acid ester, and, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof.

Substituted phenyl groups may contain one or more than one substituent in any of the positions available for substitution. Preferred substituents are nitro or halogeno, such as bromo, as well as chloro, iodo and the like; other suitable groups, such as methyl and the like, may also be attached to the phenyl radical. The organic portion in the organic sulfonyloxy group may, therefore, be represented by nitro-phenyl, e.g. 3-nitro-phenyl, 4-nitro-phenyl and the like, halogenophenyl, e.g. 4-bromo-phenyl and the like, as well as by phenyl and the like. It may also stand for another organic radical, such as an aliphatic radical, for example, lower alkyl, e.g. methyl, ethyl and the like.

Hydrolysis of the organic sulfonyloxy group in the 18,3 organic sulfonyloxy S-epi-allo-yohimbane-loo-carboxylic acid ester, may be carried out by treatment with water, preferably in the presence of an amine, especially a tertiary amine, such as, for example, an N,N,N-tri-lower alkyl-amine, e.g. N,N,N-trimethylamine, N-ethyl-N,N dimethylamine, N,N,N-triethylamine and the like, or any other suitable amine. Hydrolysis is achieved by heating the mixture to an elevated temperature, preferably in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen. Hydrolysis reaction proceeds with inversion, i.e. the 18fl-organic sulfonyloxy-3-epi-allo-yohimbane lofl-carboxylic acid ester yields upon hydrolysis according to the above procedure the 18a-hydroxy-3-epiallo-yohimbane l6fl-carboxylic acid ester.

The above 18,6-organic sulfonyloxy-3-epi-alloyohimbane 16,8-carboxylic acid esters used as the intermediates may be prepared according to known methods, for example, by esterification of an lSfi-hydroxy-S-epi-alloyohimbane l6fi-carboxylic acid ester with an organic sulfonyl halide, particularly a monocyclic aryl sulfonyl halide, such as benzene sulfonyl chloride, or a substituted benzene sulfonyl chloride, e.g. 3-nitro-benzene sulfonyl chloride, 4-nitro-benzene sulfonyl chloride, 4-bromo-benzene sulfonyl chloride and the like, in the presence of a base, particularly an organic tertiary base, e.g. pyridine, collidine and the like. In the esterification step, the base, such as, for example, pyridine and the like, may also serve as the diluent; other suitable, inert solvents may be added, if necessary. The reaction is carried out under cooling or at room temperature, preferably under the exclusion of moisture.

The l8-etherified hydroxy-S-epi-allo-yohimbane 16/8- carboxylic acid esters, salts, N-oxides or salts of N-oxides thereof may also be prepared, for example, by subjecting an IS-organic sulfonyloXy-3-epi-allo-yohimbane 16,8-carboxylic acid ester, a salt, an N-oxide or a salt of an N-oxide thereof, to solvolysis with an alcohol, and, if desired, carrying out the optional steps.

The organic portion of the organic sulfonyloxy group has the previously given meaning, and is primarily a monocyclic carbocyclic aryl group, which may be represented by phenyl, or, more particularly, by substituted phenyl. The latter is preferably a phenyl radical substituted in the 2-position, 3-position and/ or the 4-position by an electron-Withdrawing substituent, particularly nitro or halogeno, such as bromo, as well as fluoro, chloro or iodo, as well as carbo-lower alkoxy, e.g. carbomethoxy, carbethoxy and the like, carbamyl, cyano or any other suitable groups. Lower alkyl, especially methyl and the like, may also be a suitable substituent. The organic portion may, therefore, be represented by phenyl, or primarily by halogeno-phenyl, e.g. 4-bromo-phenyl and the like, or nitro-phenyl, e.g. 3-nitrophenyl, 4-nitro-phenyl and the like, as well as cyano-phenyl, e.g. 4-cyano-phenyl and the like, or di-substituted or tri-substituted phenyl radicals containing such groups. The organic radical may also stand for other organic radicals, such as an aliphatic radical, for example, lower alkyl, e.g. methyl, ethyl and th like.

Solvolysis with the alcohol may be carried out in the absence, but more preferably in the presence of an alcoholysis reagent. Such reagent is represented by an amine, such as a tertiary amine, especially an aliphatic tertiary amine, such as an N,N,N-tri-lower alkyl-amine, e.g. N,N,N-trimethylamine, N-ethyl-N,N-dimethylarnine, N,N-diethyl-N-rnethylamine, N,N,N-triethylamine and the like, an N,N,N',N-tetra-lower alkyl-lower alkylene-diamine, e.g. N,N,N',N'-tetramethyl-1,S-pentylene-diamine,

N,N,N',N' tetramethyl 1,6 hexylenediamine, N,N, N',N'-tetramethyl-1,7-heptylene-diarnine and the like, a l-lower alkyl-N,N-alkyleneimine, in which alkylene contains from four to six carbon atoms, e.g. l-methyl-pyrrolidine, l-methyl-piperidine, l-ethyl-piperidine, l-methyl- N,N-hexamethylene-imine and the like, 4-lower alkylmorpholine, e.g. 4-methyl-rnorpholine, 4-ethyl-morpho- 16 line and the like, 1,4-di-lower alkyl-piperazine, e.g. 1,4- dimethyl-piperazine and the like, or any other suitable aliphatic tertiary amine, as well as a heterocyclic base containing a tertiary nitrogen atom, e.g. pyridine, collidine and the like, or any other suitable base.

The solvolysis may be carried out using the alcohol, for example, a lower alkanol and the like, as the diluent; any other inert solvent such as, for example, p-dioxane and the like, may be added to ensure complete solution. The reaction is preferably completed at an elevated temperature, if necessary, in a closed vessel under an increased pressure, and/or in the atmosphere of an inert gas, such as nitrogen.

The solvolysis occurs with inversion; thus, an 18/3-organic sulfonyloXy-3-epi-allo-yohimbane lofi-carboxylic acid ester, upon treatment with an alcohol, yields an 18aetherified hydroXy-3-epi-allo-yohimbane l6B-carboxylic acid ester, and vice versa.

The l8-organic sulfonyloXy-3-epi-allo-yohimbane 16,8- carboxylic acid esters, salts, N-oxides or salts of N-oxides may be prepared as previously shown, for example, by esterification of an 18-hydroxy-3-epi-allo-yohimbane 16;?- carboxylic acid ester.

New and particularly suitable as intermediates are the 18,8 (halogeno phenyl) sulfonyloxy .3 epi allo yohimbane 16-carboxylic acid esters and the 18(3-(nitrophenyl)sulfonyloxy-3-epi-allo-yohimbane l6fi-carboxylic acid esters, particularly the compounds of the formula:

- in which R R R R R and R have the previously "figuration, i.e. the conversion of compounds derived from natural sources or from known totally synthetic procedures into compounds of the 18-epi-series, either according to the above-described solvolysis or the previously shown hydrolysis to the desired l8ot-hydroxy-3-epi-alloyohimbane l6fl-carboxylic acid esters used as intermediates in the etherification procedure.

Important intermediates used for the conversion of compounds with the lite-configuration into derivatives of l8a-series are those having the formulae:

l7 l8 and i the 4-position of the phenyl portion of the 18,8--halogeno-phenyl-sulfonyloxy group, or acid addition salts of such compounds. Preferred members of this group are the lower alkyl 18-O-(bromo-phenyl-sulfonyl)-reserpates,

in which the letter 12 represents one of the whole nu i particularly methyl l8-0-(4-bromo-pheny1-sulfonyl) rebers from one to seven, especially from one to three, 15 serpate, as well as Z-lower alkoxy-ethyl IS-O-(bromothe letter w represents one or" the whole numbers from phenyl-sulfonyl)-reserpates, particularly the 2-methoxyone to four, and the letter y stands for one of the whole ethyl 18-"--(4-brorno-phenyl-sulfonyl)-reserpate, or acid numbers from two to three, and in which the radical of addition salts of such compounds. Apart from being the formula -(C ll separates the two oxygen valuable intermediates, the above-mentioned ISB-organic atoms attached to such radical by at least two carbon 20 sulfonyloxy-3-epi-allo-yohimbane l-fi-carboxylic acid atoms, and R represents lower a koxy, having from esters, salts, N-oxides or salts of N-orcides thereof show one to four carbon atoms, particularly methoxy, as well sedative and tranquilizing properties and can be used as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the accordingly. like, whereby R is preferably attached to the ill-position The compounds of the present invention may also be or the ll-position, and in which the nitro group is prefprepared by removing in a A -18-etherified hydroxy-alloerably located in the 3-position or the 4-position of the yohimhene lofi-carhoxylic acid ester of a salt of such phenyl portion of the 18B-(nitro-phenyl-sulfonyloxy)- compound, the double bond extending from the 3-posisubstituent, or acid addition salts of such compounds. tion by reduction and, if desired, carrying out the option Preferred members of this group of compounds are the al steps.

lower alkyl l8-0-(nitro-phenyl-sulfonyl)-reserpates, espe- The double bond of the starting material is in the cially the methyl l8-0-(nitro-phenyl-sulfonyl)-reserpates, 3(l4)-position or in the 3(4)-position; in a free base as well as the 2-lower alkox -ethyl lS-O-(nitro-phenylor in the latter in solution in a non-polar solvent, the snlfonyl)-reserpates, particularly the Z-methoxyethyl 18- double bond is in the 3(l4)-position, Whereas in a salt, O-(3-nitro-phenyl-sulfonyl)-reserpate or Z-methoxyethyl in ne latter in solution or in the free base in solution 18-0-(4-nitro-phenyl-sulfonyl)-reserpate, or acid addiin a polar solvent, the double bond is in the 3(4)- tion salts of such compounds. position.

Another group of important intermediates is repre- In the abovedescribed starting material, the anion sentcd by the following formulae: of a salt stands primarily for the anion of a strong inorin which the letter 12 represents a whole number from ganic acid, particularly a mineral acid, such as a hydroone to seven, especially from one to three, the letter w halic acid, e.g. hydrochloric, hydrobrornic acid and the represents one of the whole numbers from one to four, like, or phosphoric acid, a halogenophosphoric acid, egg. and the yetter 2 stands for one of the whole numbers chlorophosphoric acid and the like, or perchloric acid from two to three, and in which the radical of the foror any other suitable acid; it may also represent the anion Inula -(C l-l separates the two oxygen atoms atof an organic acid. A salt with an organic acid may be tached to such radical by at least two carbon atoms, and present whenever a solution of the starting material in an It, represents lower allqoxy, having from one to four organic acid, e.g. acetic acid and the like, is used in the carbon atoms, particularly methoxy, as well as ethoxy, above-described removal procedure. The conversion of n-propyloxy, isopropyloxy, n-hutyloxy and the like, Where one form into the other may be carried out according by R is preferably attached to the ill-position or the to known methods. Thus, a free compound yields the ll-position, and in which brorno is preferably located in salt upon reaction with an acid, or by treatment of the salt with an alkaline reagent, particularly ammonia, preferably in an anhydrous medium, or any other suitable base, the free compound may be obtained. In the previously described method, acidic conditions prevail; therefore, whenever the starting material is given to the reaction mixture in the form of the free compound, the salt is formed in situ.

The removal of the double bond is carried out according to known reduction methods yielding the desired 18- etherified hydroxy-3-epi-allo-yohimbane 16,8 carboxylic acid ester compounds, particularly by treating a solution of the starting material in an acid, such as, for example, acetic acid (preferably in the form of aqueous acetic acid), perchloric acid and the like, with a metal. Together with the acid, the metal furnishes the reducing reagent capable of reducing the double bond; zinc, in the presence of an acid, e.g. acetic, perchloric acid and the like, yields a very useful reducing reagent. Zinc in the presence of perchloric acid, which may be used in an aqueous mixture or in admixture with another acid, e.g. acetic acid and the like, represents the preferred reagent; this reagent is particularly suitable, because the rate of reduction is fast and any contact of the starting material, as well as the reduction product with the acidic medium can be kept to a minimum. Organic diluents, such as ether-s, e.g. tetrahydrofuran, p-dioxan and the like, lower alkanones, e.g. acetone and the like, or any other suitable solvent may be present as additional diluents, if desired, together with water. The reaction may be carried out at room temperature, or, if nemssary, under cooling or at an elevated temperature.

The product of the reduction procedure may be isolated, for example, by neutralizing the acidic reaction mixture with an alkaline reagent, e.g. ammonia and the like, if desired, after removing the solvent or part of it, and extracting the organic material with a suitable solvent, e.g. methylene chloride and the like, or by any other appropriate isolation method.

The above-mentioned starting materials may be prepared, for example, by reacting an 18-etherified hydroxy- 3-oxo-2,3-seco-allo-yohimbane 16,8-carboxylic acid ester with a ring-closing reagent, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a free compound into a salt thereof.

Ring closure of the above-described 2,3-seco-allo-yohimbane compounds may be carried out according to known methods, for example, by treatment with an acidic ring closing reagent, for example, a phosphoric acid, e.g. polyphosphoric acid and the like, a phosphorus halide, e.g. phosphorus trichloride, phosphorus pentachloride, advantageously a phosphorus oxyhalide, e.g. phosphorus oxychloride and the like,

The 2,3-seco-allo-yohimbane compounds used as the diazo compound in the presence of fluoboric acid or any other suitable Lewis acid. Etherification may also be achieved according to other known procedures, for example, by treatment with other reagents suitable for the etherification of a secondary hydroxyl group. Such reagents are,-for example, reactive esters formed byhydroxylated compound with strong acids, such as inorganic acids, e.g hydrochloric, hydrobromic, ,hydriodic, sulfuric acid and the like, or with organic acids, particularly strong organic sulfonic acids, e.g. p-toluene sulfonic acid and the i like, which reagents are preferably used in the presence of reagents facilitating the etherification procedure. 7 The above" etherification procedure is particularly suitable for .the preparation; of 3-oxo-2,3-seco-allo-yohimbane compounds which can be prepared directly from products obtained according to known totally synthetic methods.

The intermediate 3-oxo-2,3-seco-allo-yohimbane compounds may also be prepared by esterifying in an 18-hydroxy-3-oxo-2,3-seco-allo-yohimbane 16/3-carboxylic acid ester the free hydroxyl group by treatment with an organic sulfonic acid halide, particularly a monocyclic carbocyclic aryl sulfonyl halide, as well as an aliphatic sulfonic acid halide, and subjecting a resulting lit-organic sulfonyloxy-3- oXo-2,3-seco-allo-yohimbane 16fl-carboxylic acid ester to solvolysis with an alcohoL. Esterification with an organic sulfonic acid halide, for example, with a (halogeno-phenyl)sulfonyl chloride, a (nitro-phenyD-sulfonyl chloride and the like, is carried out as previously shown, for example, in the presence of an organic base, e.g. pyridine and the like. Alcoholysis of the l8-organic sulfonyloxy group may be achieved according to the procedure described hereinbefore, preferably in the presence of a base, such as an organic amine, e.g. N,N,N-diethylarnine, pyridine and the like, As has been shown hereinbefore, solvolysis of an 18-organic sulfonyloxy group occurs with inversion at the 18-carbon atom. This procedure is particularly suitable for the preparation of 3-oxo-2,3-secoyohimbane compounds with an 18-etherified hydroxyl group having the ot-configuration, i.e. compounds, which can be prepared from products obtained according to known totally synthetic methods.

The 18a-hydroxy-3-oxo-2,3-sec0-allo yohimbane 16/ carboxylic acid esters, which compounds can be used either in the above etherification procedure to form the 18aetherified hydroxy-3-oxo-2,3-seco-allo-yohimbane l6B-carboxylic acid esters or in the esterification to the 1806-01- ganic sulfonyloxy-3-oxo-2,3-seco-allo-yohimbane IGfl-carboxylic acid esters, may be obtained, for example, by hydrolysis of ISfi-Organic sulfonyloXy-3-oxo-2,3-seco-alloyohimbane 16fi-carboxylic acid esters with water, preferably in the presence of a base, such as an organic amine.

Such hydrolysis procedure is carried out according to methods previously described in detail.

The 18-etherified hydroxy-3-oxo-2,3-seco allo yohimbane 16,8-carboxylic acid esters, used as the intermediates for the preparation of the starting materials may also be prepared, for example, by ring closure of an 18-etherified hydroxy-3-lower alkoxy-3-oxo-2,3;3,4-bis-seco-allo-yohimbane l6fi-carboxylic acid ester or a salt thereof. Ring closure may be achieved according to known methods, for example, by treatment of the ester with a carboxylic acid anhydride, e.g. acetic acid anhydride and the like, or any other analogous ring-closing reagent.

The 2,3;3,4-bis-seco-allo-yohimbane compounds used in the above procedure may be prepared, for example, by etherifying in a 3I3-hYdI'OXY-7-OXO-10:,2B,3ot,4,7,8,90c,l00 r octahydro-naphthalene lfl-carboxylic acid ester the free hydroxyl group according to previously given methods used for the etherification of secondary hydroxyl groups, to form a 3,8-etherified hydroxy-7-oxo-1a,2[3,3a,4,7,8,9u, 10or-octahydro-naphthalene LB-carboxylic acid esters. Or, a Sfl-hydroxy 7 -.oxo lot,2fi,3a,4,7,8,9a,l0a octahydronaphthalene lfi-carboxylic acid ester may be reacted with an organic sulfonic acid halide, preferably a monocyclic carbocyclic aryl-sulfonyl chloride, in the presence of an organic base, and a resulting 3fl-organic sulfonyloxy-7- OXO-1a,2 3,3ot,4,7,8,9ot,lOct-OCtahYdI'O-HaPhthalEIIB 1B carboxylic acid ester may be subjected to solvolysis with an' acid hydrate in an aqueous medium, to form 5;3-aldehydo- 3-etherified hydroxy-SB carboxymethyl lu,2,8,3,4,5u,6ahexahydro-benzene Ifi-carboxylic acid esters. The free carboxyl group of the carboxymethyl portion is then esterified, for example, with a lower diazoallrane, e.g. diazomethane, diazoethane and the like, to form the desired 5,6- aldehydo-3-etherified hydroxy 6B carbo lower alkoxymethyl-1a,2[3,3,4,5a,6a-hexahydro-benzene lfi-carboxylic acid esters, which compounds are then reacted with a tryptamine, preferably in solution with an inert solvent, e.g. benzene and the like, to yield A -18-etheriiied hydroxy- 3-lower alkoxy-3-oxo-2,3;3,4-bis-seco-allo-yohimbene 16B- carboxylic acid esters. Upon treatment with a reducing reagent, for example, with a borohydride, e.g. sodium borohydride and the like, in an inert solvent, such as a lower alkanol, e.g. methanol, ethanol and the like, and, if necessary, in the presence of an activator, e.g. aluminum chloride and the like, the Schithbase type double bond is reduced, and the desired 18-etherified hy roxy-3-lower ZlikOX}3-OXO-2,3,3,4-l)lS-SGCO-EtllO f/Ollifllbfiilfi: IGB-carboxylic acid esters are formed, in which the esterified carboxyl groups may be partially or totally hydrolized. Hydrolized carboxyl groups may subsequently be re-esteriiied, for example, by treatment with a lower aliphatic diazohydrocarbon, such as a lower diazoalkane, particularly diazomethane, as well as diazocthane and the like, or any other suitable ciazo-reagent.

The 5B-aldehydo-3etherified hydroxy-dd-carbo-lower alkoxy-rnethyl- 1 [1,2 [3,3,4,5 04,6u-hEX2Ll1YdIO-b6il26l16 1 B-carboxylic acid ester may also be prepared, for example, by directly etherifying, or esterifying with an organic sulfonic acid hali e and subsequently alcoholizing with an alcohol, the free hydroxyl group in a 3-hydroXy-7-oxo-1a, 2,8,3,4,7,8,9a,104x octahydro naphthalene I/B-carboxylic acid ester, which reactions are carried out according to the previously described methods. A resulting 3-etherified hYdIOXYJ-OXO-1a,2[3,3,4,7,3,9oz,10cc octahydro naphthalene lfi-carboxylic acid ester is then subjected to the treatment of ozone in the presence of an inert organic solvent, for example, in glacial acetic acid, ethyl acetate and the like, and at temperatures between 0 and about -60 to effect ozonation, the excess ozone is removed from the reaction mixture, for example, by bubbling an inert gas, e.g. nitrogen and the like, through the reaction solution, and the resulting ozonide is decomposed by adding Water at room temperature to form the desired 5fl-aldehydo-3etherified hydroxy 65 carboxymethyl-l01,25,3,4,5a,6a-hexahydrobenzene 1B carboxylic acid ester, in which the free carboxyl group is then esterified as previously shown to yield the desired intermediate, which is condensed with the tryptamine C0111- pound.

The etherifieation of a free hydroxyl group, with or without simultaneous inversion, may also be carried out at any other suitable step of the above shown procedures leading to the desired intermediates for the preparation of the starting materials.

The A -18-etherified hydroxy-allo-yohimbene 16B-carboxylic acid esters or salts thereof, which compounds are used as starting materials for the preparation of the l8-etherified hydroxy-3-epi-allo-yohimbane ISB-carboxylic acid esters according to the previously described procedure, may also be prepared, for example, by ring closure of an l8-organic sulfonylox -3-oXo-2,3-seco-alloyohimbane 16,8-carbo2rylic acid ester and subsequent solvolysis of a resulting A -l8-organic sulfonylox -allo-yohimbene 16,8-carboxylic acid ester, or a salt thereof, with an alcohol to yield the desired starting material, i.e. the A -IS-etherified hydroXy-allo-yohimbene 16fi-carboxylic acid esters. Ring closure (preferably With phosphorus oxychloride) and alcoholysis (preferably in the presence of an organic amine) are carried out according to methods described in detail hereinbefore.

The A -18-etherified hydroxy-allo-yohirnbene 16,8-carboxylic acid esters or salts thereof used as the starting materials in the above procedure may also be prepared, for example, by etherifying in a N-lB-hydroxy-allo-yohimbene 16fl-carboxylic acid ester or a salt thereof, the free hydroxyl group, and, if desired, carrying out optional steps. The above etherification may be carried out according to previously described procedures, for example, by treatment with a diazo compound in the presence of a strong Lewis acid, e.g. fluoboric acid and the like, or any other etherification procedure capable of etherifying a secondary hydroxyl group.

The starting materials, which are used in the above procedure, are new and are intended to be included within the scope of the present invention. They are primarily those of the formulae:

in which R R R R R R and R have the pre viously given meaning, in which a double bond extends from the S'position, or salts thereof.

Preferred groups of starting materials may be represented by the formulae:

in which formulae the letters m, n, w, x, y and z and R have the previously given meaning, and in which a double bond extends from the 3-nosition, or salts of such com- 35 pounds. Salts are especially those, in which the anion is derived from an inorganic, particularly a mineral, acid, such as one of those mentioned hereinabove, e.g. hydrohalic acids, e.g. hydrochloric, hydrobromic acid and the like, phosphoric acid, halogeno-phosphoric acids, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable inorganic acid, as well as organic acids, e.g. acetic acid and the like. These compounds are represented, for example, by lower alkyl 18-O-lower alkyl-3- dehydro-reserpates, in which lower alkyl has from one to seven carbon atoms, especially by the methyl 18-O-lower alkyl-3-dehydro-reserpates, in which lower alkyl has from one to three carbon atoms, and by the lower alkoxylower alkyl 18-epi-O-lower alkoXy-lower alkyl-3-dehydroreserpates, in which lower alkyl has from two to three carbon atoms and separates lower alkoxy having from one to four carbon atoms, from the 16,8-carboxyl group and the 18a-oxygen atom, respectively, by from two to three carbon atoms, or salts thereof.

In the previously mentioned methods for the preparation of the starting materials, new and important intermediates are being formed, which are intended to be included within the scope of this invention. Particularly useful are the IS-etherified hydroxy-3-oxo-2,3-seco-alloyohimbane 16fi-carboxylic acid esters, particularly those having one of the formulae:

in which R1, R2, R3, R4, R5, R5, R5 and R7 have the previously given meaning.

Preferred groups of these intermediates are represented by the formulae:

in which the letters in, n, w, x, y as z, and R, .ave the previously given meaning. These compounds are represented by lower alkyl 18-G-lower allryl3-oxo-2,3- seco-reserpates, in which lower allcyl has from one to seven carbon atoms, especially by the methyl l S-O-lower allryl-3cite-2,3-seco-reserpates, in which lower alkyl has from one to three carbon atoms, by lower alkyl lg-spi-C- lower allryl-3-oXo-2,El-seco-reserpates, in which lower alkyl has from one to seven carbon atoms, especially by the methyl l -epi-O-lower allryl-3bro-2,3-scco-reserpates, in which lower alkyl has from one to three carbon atoms, and by lower alkoXy-lower allryl l -epi-l-lower allroxylower alkyl-lono-Zjsecoaeserpates, in which lower alkyl has from two to three carbon atoms and separates lower alltoxy from the 16fi-carboxyl group and the lfiwonygcn atom, respectively, by from two to three carbon atoms.

The compounds of the present it cation, as well as the starting materials and intermediates used in their formation, may be present in the form of mixtures of racemates, single racemates or antipodes.

Mixtures of racemates of final products or starting materials may be separated into the single racernates on the basis of physico-chemical differences, for example, by fractionated crystallization and the like.

Racemates of intermediates and roducts may be resolved into antipodes. Racemates of final products or intermediates, forming acid addition salts, may be resolved, for example, by treating a solution of the free racemic base in a suitable inert solvent with one of the optically active forms of an acid containing an asymmetric carbon atom, or a solution thereof. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D- and Ltartaric acid, as Well as the optically active forms of di-o-toluyl tartaric, malic, mandeiic, camphor-lO-ntlfonic, quinic acid and the like. A salt may then be isolated, which is formed by the optically active acid with one of the optically active forms of the base. The optically active forms may also be obtained by resolving racemates using biochemical methods. From an optically active salt, the free and optically active compounds may be obtained according to known methods used for the conversion of a salt into a free compound, for example, as outlined hereinbelow. A resulting opt cally active base may be converted into an addition salt with one of the acids mentioned hereinbefore, or into an N-oxide or an acid Ion salt of an N-OXlCl6 thereof, as shown hereinbe- The compounds of this invention or the N-oxides there of may be obtained in the form of the free bases or as the salts thereof. A salt, including a salt of an N-oxide, may be converted into the free base, for example, by reacting the former with a basic reagent, such as, for example, aqueous ammonia, silver oxide and the like, or an ion exchange resin. A free base or the N-oxide thereof may be converted into the therapeutically useful acid addition salts thereof by treating it with one of the inorganic or organic acids mentioned hcreinbefore; the reaction may be carried out, for example, by treating a solution of the free base in a suitable inert solvent with the acid or a solution thereof and isolating the resulting 26 salt. The salts may also be obtained as the semiby rates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the L7. is.

N-oxides of the compounds of the present invention may be formed according to known methods; for example, a resulting compound, preferably a solution thereof in inert solvent, may be reacted with an N-oxidizing reagent, such as, for example, hydrogen peroxide, ozone, persulfuric acid, or more especialli an organic peracid, such as an organic percarboxylic acid, e.g. peracetic, perbenzoic, monoperphthalic acid and the like, or a persulfonic acid, eg. p-toluene persulfonic acid and the like. inert solvents used in the preparation of the N-o ricles are, for example, halogenated lower ailranes, e=.g. methylene chloride, chloroform, ethylene chloride and the like, lower allranols, cg. methanol, ethanol and the like, or any other suitable solvent. in the N-oxidation reaction an excess of the oxidation reagent and/or an increase in temperature should be avoided in order to prevent oiridative degradation.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out. it also includes any new intermediates, which may be formed in one of the procedures outlined hereinbefore.

in the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

This is a continuation-in-part application of our application Serial No. 110,321, filed May 16, 1961, which in turn is a continuation-impart application or" our application Serial No. 73,494, filed December 5, 1960, which in turn is a continuation-input application of our application Serial No. 46,875, tiled August 2, 1960, now abandoned, which in turn is a continuationdn-part application of our application Serial No. 37,697, file lune 20, 1960, which in turn is a continuation-in-part application of our application Serial No. 837,357, filed September 1, 1959, now abandoned, which in turn is a continuation-in-part application of our application Serial No. 833,187, filed July 29, 1959, now abandoned. The present application is also a continuation-in-part application of our application Serial No. 110,320, filed May 16, 1961, which in turn is a continuationdn-part application of our application Serial No. 73,490, filed December 5, 1959, new abandoned, which turn is a contiiutation-in-part application of our application Serial No. 46,911, filed August 2, 1960, now abandoned.

The following examples illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade.

Example 1 To a solution of 2.48 g. of meth l reserpate in 400 ml. of methylene chloride, maintained at --16 to -15, is added 66 m1. of a fiuoboric acid solution while stirring. (The latter is prepared as follows: Commercially avail able fifty percent aqueous lluoboric acid is concentrated by partial evaporation under reduced pressure to an approximately 14 N solution, determined by titration with a standard sodium hydroxide solution. A stock solution of approximately 0.1 N strength is prepared by dissolving 1 ml. of the concentrated fluoboric acid in a mixture of 110 ml. of absolute ether and 30 ml. of methylene chloride.) A small precipitate forms during the addition, which represents, probably, a salt of methyl reserpate with the acid.

A solution of diazomethane in methylene chloride (69 ml. of an 0.348 N solution) is added to the stirred reaction mixture over a period of about five minutes; during the addition the temperature is maintained at about 10. The previously mentioned precipitate dissolves again. An additional 1 ml. of the stock solution is stirred for a few more minutes. 2 ml. of glacial acetic acid is added with the intent to destroy any excess of diazomethane.

The solution is washed twice with five percent aqueous sodium carbonate and once with saturated aqueous sodium chloride, the organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure, whereupon 2.24 g. of a tan, solid material can be recovered, which is purified as follows: As much as possible of the residue is dissolved in 50 to 60 ml. of benzene at room temperature; the undissolved material is filtered ofii. The filtrate is chromatographed on about 40 g. of aluminum oxide (Woelm, neutral, activity I); the desired methyl IS-O-methyl-reserpate is eluted with benzene, containing 0.2 percent of methanol. The oily, yellow solid is washed with cold ether and recrystallized from a 1:3- mixture of benzene and cyclohexane, using charcoal as a decolorizing agent, Ml. 228231 (with decomposition). I

The purification step may also be carried out as follows: 7.5 g. of benzene-soluble material, obtained from the tan, solid product, is dissolved in r ml. of benzene and placed on a column containing 240 g. of aluminum oxide (Woelm, neutral activity Il-lll). The column is washed with about 500 ml. of benzene, and subsequently with about 3,000 ml. of methylene chloride and about 2,000 ml. of methylene chloride containing 0.5 percent of methanol. The fractions obtained with methylene chloride and the first fractions eluted with the methylene chloride-methanol mixture are combined after evaporation of the solvent, and the residue is recrystallized using a lz3-mixture of benzene and cyclohexane and charcoal as an adsorbent. The resulting, pure methyl IS-O-methylreserpate of the formula:

ll 5 0 our;

melts at 235-237 M1 -111 (in chloroform) and is identical with the above-described product.

Example 2 Substitution of the diazomediane solution in Example 7 1 by 113 ml. of an 0.212 N solution of diazoethane in Example 3 A solution of 4.25 g. of n-propyl reserpate and 130 ml. of the stock fiuoboric acid solution described in Example 1 is treated with about five to six times the theoretical amount of a diazomethane solution in methylene chloride at -10". The reaction mixture is Worked up as shown in Example 1; the n-propyl lS-O-methyl-reserpate melts at l64l65 after recrystallization from a 1:4-

mixture of benzene and cyclohexane, [a] =93 (chloroform); yield: 0.25 g.

n-Propyl IS-O-ethyhreserpatc may be prepared, for example, by reacting n-propyl reseipate with n-diazoethane in the presence of fluoboric acid.

The starting material may be prepared as follows: Gaseous n-diazopropane is distilled from its ether solution into a suspension of 20 g. of reserpic acid in a lzl-mixture of chloroform and ethanol. Any excess of n-diazopropane is decomposed with acetic acid, the solvents are evaporated under reduced pressure and the residue is poured into 800 ml. of water containing 20 ml. of concentrated aqueous ammonia. A white crystalline precipitate is obtained, which is washed with water to yield the n-propyl. reserpate, M. P. 164-l66.

Example 4 By replacing in Example 1 the methyl reserpate by 2.56 g. of ethyl reserpate and treating a mixture of the latter and a fluoboric acid preparation in methylene chloride with a diazo-methane solution as shown in Example 1, the desired ethyl IS-O-methyl-reserpate can be obtained.

When treated with other lower diazo-alkanes, e.g. diazo-ethane, n-diazopropane, n-diazobutane and the like, according to the above rocedure, ethyl reserpate yields other ethyl IS-O-lower allryl-reserpates, such as ethyl IS-O-ethyl-reserpate, ethyl 18-O-n-propyl-reserpate, ethyl l8-O-n-butyl-reserpate and the like.

Example 5 Treatment of a solution of 2.67 g. of isopropyl reserpate and 66 ml. of standard fluoboric acid preparation in methylene chloride with a diazomethane solution in met ylene chloride at below -10 according to the proseduce of Example 1, results in the formation of isopropyl l8-O-methyl-reserpate.

Upon treatment of isopropyl reserpate, with n-diazopropane in the presence of fiuoboric acid, isopropyl 18-O- n-propyl-reserpate is formed.

The starting material used in the above reaction may be prepared as follows: A mixture of 10 g. of methyl reserpate, 500 ml. of isopropanol and 20 drops of benzyl trimethyl ammonium hydroxide is refluxed for 2 /2 hours. After standing at room temperature for several hours, a white precipitate (needles) is formed, which is removed by filtration. The filtrate is evaporated to dryness, the foamy residue is taken up in 500 ml. of water containing 5 ml. of concentrated aqueous ammonia. The aqueous mixture is extracted with methylene chloride, the organic solvent is passed through a column containing a diatomaceous earth preparation and is then evaporated to dryness under reduced pressure. The residue is crystallized by the addition of diethyl ether, the crystalline material is filtered oil, dried and identified as isopropyl reserpate, MI. 214-216".

Other lower alkyl 18-O-methyl-reserpates, which may be prepared according to the aforementioned procedures are, for example, n-butyl l8-O-methyl-reserpate, n-butyl 18-O-ethyl-reserpate, iso'outyl 18-O-methyl-reserpate, isopentyl IS-Q-methyl-reserpate, n-hexyl 18-O-methyl-rcserpate and the like. The starting materials used for the preparation of the above compounds are known or may be obtained according to methods used for the known compounds, particularly by treatment of reserpic acid with lower diazo-alkanes; isobutyl reserpate melts at -148 and isopentyl reserpate at l35l38, whereas n-hexyl reserpate has a melting point of 117-118".

29 Example 6 To a solution of 1.5 g. of methyl IS-O-methyl-reserpate in 25 ml. of acetone is added dropwise concentrated hydrochloric acid while stirring. The addition is carried out at room temperature and is interrupted after the solution becomes acidic to Congo Red test paper. Crystallization occurs upon scratching, the crystalline material is filtered off and washed with cold acetone. 1.5 g. of the methyl IS-G-methyl-reserpate hydrochloride is obtained, M.P. 237-242" (with decomposition).

Example 7 To a vigorously stirred solution of 5.0 g. of methyl deserpidate in 800 ml. of methylene chloride, is added a mixture of 158 ml. of diethylether, 43 ml. of methylene chloride and 1.4 ml. of concentrated aqueous fiuoboric acid. The solution is then cooled to -1l in an ice-salt bath, and 32 r ml. of a solution of diazomethane in methylene chloride is added in such manner that the ratio of diazoniethane to methyl deserpidate is 6:1. During the addition the temperature is kept between 7.5 and 11; stirring is continued for an additional twenty minutes and is then allowed to stand while cooling. After 1%. hours, the reaction mixture is washed with 850 ml. of a percent aqueous sodium carbonate solution and 350 ml. of a saturated aqueous sodium chloride solution, and the aqueous washes are extracted with methylene chloride, the organic extract is combined with the organic reaction solution, and the combined organic solutions are dried over sodium sulfate for 45 minutes. The organic solvent is evaporated, the residue is dissolved in 50 ml. of warm benzene, the insoluble material is filtered oil: and the filtrate is placed on a column containing 150 g. of aluminum oxide (activity Ill-Ill, neutral). The following fractions are collected: 500 ml. of benzene (fraction 1), 3000 m1. of methylene chloride (fractions 2 to 7 at 500 ml. each), 3000 ml. of methylene chloride, containing 0.5 percent of methanol (fractions 8 to 13 at 500 ml. each), 1500 ml. of methanol. Fractions 8 to 13 are combined and recrystallized from diethylether to yield 0.1 g. of methyl 18-O-methyl-deserpidate, MP. 114- 115 C.; [a] =137 (chloroform).

Compounds, such as ethyl 18-O-methyl-deserpidate, ethyl 18-O-ethyl-deserpidate, ethyl 18-O-n-propyl-deserpidate, n-propyl 18-O-methyl-deserpidate, n-propyl 18- O-ethyl-deserpidate, isopropyl IS-Omethyl-deserpidate, isopropyl 18-O-n-butyl-deserpidate, nbutyl ISO-methylcleserpidate, secondary butyl 18-O-methyl-deserpidate, npentyl 18-O-methyl-deserpidate, methyl IS-O-ethyldeserpidate, methyl l8-O-propyl-deserpidate, methyl 18- O-isopropyl-deserpidate, methyl IS-n-butyI-deserpidate, methyl lti-O-secondary butyl-deserpidate and the like, are formed upon treatment of the corresponding lower alkyl deserpidates with lower diazo alkanes according to the procedure of Example 1, or according to one of the other procedures previously described.

Example 8 By reacting a solution of 0.92 g. of Z-methoxyethyl reserpate and 22 ml. of the standard fluoboric acid preparation in methylene chloride with diazomethane as shown in Example 1, the desired Z-methoxyethyl 18'0- rnethyl-reserpate can be formed.

The starting material may be prepared as follows: To a mixture of 226 g. of a 33 percent aqueous solution of Z-methoxyethylamine and 150 ml. of diethyl ether, kept at 5 to in an ice bath, is added dropwise 54 g. of ethyl chloroformate. 100 g. of a cold 40 percent acqueous solution of sodium hydroxide and a second portion of 54 g. of ethyl chloroformate are given to the mixture, which is stirred for one hour. The other layer is separated, the aqueous phase is extracted with 100 ml. of diethyl ether, and the two ether solutions are combined and dried over potassium carbonate. The solvent is evaporated under reduced pressure and the ethyl N-(Z- Eli) methoxyethyl)-carbamate is distilled at -106/ 17 to 20 mm.

To a solution of 33 g. of ethyl N-(2-methoxyethyl)- carbamate in 200 ml. of diethyl other are added 25 g. of cracked ice and a solution of 81 g. of sodium nitrite in ml. of water. While keeping the temperature below 15, g. of 35 percent aqueous nitric acid is added carefully over a period of one hour. The ether layer is separated, washed with water and aqueous potassium carbonate and then dried over potassium carbonate. The residue, obtained after evaporation of the solvent under reduced pressure, represents the ethyl N-(Z-methoxyethyl)-N-nitroso-carbamate, which is used without further purification.

A gently refluxing solution of 5 g. of potassium hydroxide in 15 g. of methanol and 150 ml. of diethyl ether is treated with a solution of 15.5 g. of ethyl N-(2- methoxyethyl)-N-nitroso-carbamate in 50 ml. of diethylether, which is added dropwise over a period of one hour. After refluxing for 5 minutes, 100 ml. of water is added and the yellow ether solution, containing the Z-methoxy-diazoethane, is separated.

The above other solution of 2-methoxy-diazoethane is reacted with small portions of a slurry of resperic acid in methanol until no further reaction can. be observed. A few drops of acetic acid are added, the solution is evaporated under reduced pressure and the residual oil is dissolved in ethyl acetate. Upon addition of petroleum other a precipitate is formed, which is filtered 01f, dissolved in methylene chloride, which solution is washed with aqueous ammonia and filtered through a small column containing a diatomaceous earth. The residue, obtained after evaporation of the solvent, is crystallized from ethyl acetate to yield the 2-methoxyethyl reserpate, MP. 183-185".

Other lower alkoxy-lower alkyl 18-O -lower alkylreserpates and lower alkoxy-lower alkyl-deserpidates, in which lower alkoxy is separated from the carboxyl group by from two to three carbon atoms, which may be prepared according to the previously given procedure by replacing the starting material by other intermediates are, for example, Z-ethoxyethyl 18-O-methyl-reserpate, 2- ethoxyethyl 18-O-n-propyl-reserpate, 2-n-propyloxyethyl lS-O-methyl-reserpate, 2-isopropyloxyethyl IS-O-methylreserpate, S-methoxypropyl IS-O-methyl-reserpate, 2- methoxypropyl IS-O-methyl-reserpate, 2-methoxyethyl 18-O-ethyl-reserpate, Z-methoxyethyl 18-O-n-propyl-reserpate, 2-rnethoxyethyl 1S-O-methyhdeserpidate, 2-methoxyethyl IS-O-ethyl-deserpidate, Z-ethoxyethyl 18-O- methyl-deserpidate and the like.

Other compounds having a lower alkoxy-lower alkyl esterified carboxyl group, and which may be prepared according to one of the previously described methods, are, for example, lower alkoxy-lower alkyl 18-O-lower alkoxy-lower alkylreserpates, in which lower alkoxy is separated from the lfi-carboxyl group and the lit-oxygen atom, respectively, by from two to three carbon atoms, e.g. 2-methoxyethyl 18-O-(2-methoxyethyl)-reserpate, Z-methoxyethyl 18-0-(Z-ethoxyethyl)-reserpate, 2-methoxyethyl 18-0-(Z-methoxypropyl)-reserpate, Z-methoxyethyl 18-0-(2-isopropyloxyethyl)-reserpate, Z-methoxyethyl 18-0-(Z-rnethoxypropyl)-reserpate, 2-ethoxyethyl IS-O-(Z-methoxyethyl)-reserpate, Z-ethoxyethyl 13-O- (Z-ethoxyethyl)-reserpate, 2-ethoxyethyl 18-O-(3-meth oxypropyD-reserpate, 2-n-propyloxyethyl 18-O-(2-methoxyethyl)-reserpate, 2-isopropyloxyethyl 18-O-(2-ethoxyethyl)-reserpate, 2'methoxypropyl 18 0 (2 methoxyethyl)-reserpate, Z-methoxypropyl 18-O-(2-ethoxyethyl)- reserpate, 3-methoxypropyl 18-O-(2-methoxyethyl)-reserpate, 3-ethoxypropyl 18 O-(3-methoxypropyl)-reserpate and the like, lower alkoxy-lower alkyl l8-O-lower alkoxylower alkyl-IO-methoxy-deserpidates, in which lower alkoxy is separated from the 16-carboxyl group and the 18-oxygen atom, respectively, by from two to three carbon atoms, e.g. 2-rnethoxyethyl l0-methoxy-18-O-(2- methoxyethyl) deserpidates, 2 methoxyethyl 18-0-(2- ethoxyethyl)-lO-rnethoxy-deserpidate, Z-methoxyethyl 18- O-(Z-ethoxypropyl)--methoxy-deserpidate, Z-methoxyethyl 10-methoxy-1 8-O-( B-methoxypropyl) -deserpidate, 2-ethoxyethyl IO-methoxy- 1 8-0- (Z-methoxyethyl) -deserpidate, Z-methoxypropyl 10-methoxy-18-O-(Z-methoxyethyl)-deserpidate, 3-methoxypropyl IO-methoxy-lS-O- (Z-methoxyethyl)-deserpidate and the like, lower alkoxylower alkyl 18-O-lower alkoxy-lower alkyl-deserpidates, in which lower'alkoxy is separated from the 16-carboxyl group and the 18-oxygen atom, respectively, by from two to three carbon atoms, Z-methoxyethyl 18-O-(2-n1ethoxyethyl)-deserpidate, Z-methoxyethyl 18-O-(2-ethoxyethyl)- deserpidate, Z-methoxyethyl 18-O-(2-methoxypropyl)- deserpidate, Z-methoxyethyl 18-0- 3-methoxypropyl deserpidate, Z-methoxyethyl l8-O-(3-ethoxypropyl)-deserpidate, Z-ethoxyethyl 1S-O-(Z-methoxyethyl)-deserpidate, Z-ethoxyethyl 18-O-(2-ethoxyethyl)-deserpidate, Z-n-propyloxyethyl l8-O-(2-methoxyethyl)-deserpidate, Z-n-butyloxyethyl 18-O-(2-methoxyethyl)-deserpidate, 2- methoxypropyl 18-O-(2-methoxyethyl)-deserpidate, 2- methoxypropyl 18 O (2 ethoxyethyl) deserpidate, 3- methoxypropyl 180-(2-methoxyethyl)-deserpidate, 3- ethoxypropyl 18-O-(2-methoxyethyl)-deserpidate and the like, and acid addition salts thereof.

Example 9 To a solution of 4.55 g. of methyl reserpate in 730 ml. of methylene chloride is given 121 ml. of the concentrated fluoboric acid solution described in Example 1. 150 ml, of an 0.3 molar solution of n-diazobutane is added, and the reaction mixture is treated and worked up as shown in Example 1. The resulting methyl l8-O-n-butyl-reserpate is recrystallized from a mixture of benzene and cyclohexane, MP. 219-221 (with decomposition).

In the above example, n-diazobutane may be replaced by other lower diazo-alkanes, e.g. n-diazopropane, diazoisopropane, diazo-isobutane, n-diazopentane and the like; upon reacting these reagents with methyl reserpate in the presence of fluoboric acid as shown hereinabove, methyl 1S-O-n-propyl-reserpate, methyl 18-O-isopropylreserpate, methyl 18-O-isobutyl-reserpate, methyl 18-0- n-pentyl-reserpate and the like, are formed and may be converted into their acid addition salts, e.g. hydrochloride and the like as shown in Example 6.

Example 10 A solution of 1.25 g. of methyl IO-methoxy-deserpidate and about ml. of the fluoboric acid preparation described in Example 1 in methylene chloride, when treated with a diazoethane solution in methylene chloride at a temperature below 10 according to the method outlined in Example 1, yields the desired methyl 10-methoxy- IS-O-ethyl-deserpidate.

Upon treatment with hydrochloric acid according to the method described in Example 6, the methyl 10- methoxy-lS-O-ethyl-deserpidate hydrochloride is formed.

Other lower alkyl ISO-lower alkyl-IO-methoxy-deserpidates, such as, for example, methyl 18-O-n-propyl- IO-methoxy-deserpidate, methyl 10-methoxy-1S-O-n-butyl-deserpidate, ethyl 10-methoxy-18-O-methyl-deserpidate, n-propyl IO-methoxy-l8O-methyl-deserpidate, isopropyl 10-methoxy-IS-O-methyl-deserpidate and the like, or the salts thereof, are prepared by treating appropriate lower alkyl IO-methoxy-deserpidates with the desired lower diazo-alkanes according to the method described in detail in Example 1.

Other 18,8-etherified hydroxy-3-epi-allo-yohimbane 16B- carboxylic acid esters, which may be prepared according to one of the above-described methods by selecting the appropriate starting materials, are, for example,

lower alkyl 18-O-lower alkyl-5-'nethy1-reserpates,

e.g. methyl S-methyl-lS-O-methyl-reserpate, "methyl 18-0ethyl-5-methyl-reserpate, e hyl 5 met yl-l8-O-methyl-reserpate and the like,

, .32 lower alkyl 18-Olower alkyl-5-methyl-deserpidates, e.g. methyl S-methyl-l8-O-methyl-deserpidate,

methyl S-methyl-18-O-n-propyl-deserpidate,

ethyl S-methyl-IS-O-methyl-deserpidate and the like,

lower alkyl 18-O-lower alkyl-6-methyl-reserpates,

e.g. methyl 6-methyl-18-O-methyl-reserpate,

methyl 18-O-ethyl-6-methyl-reserpate,

methyl 18-0-n-butyl6-methyl-reserpate,

ethyl 6-methyl-lS-O-methyl-reserpate,

n-propyl 6-methyl-18O-methyl-reserpate,

lower alkyl 18-O-lower alkyl-6-1nethyl-deserpidates,

e.g. methyl 6-methyl-1S-O-methyl-deserpidate,

methyl 6-methyl-18-O-n-propyl-deserpidate,

ethyl G-methyl-lS-O-methyl-reserpate and the like,

lower alkyl l8-O-lower alkyl-9-methyl-deserpidates,

e.g. methyl 9-methyl-18-O-methyl-deserpidate,

methyl 13-O-ethyl-9-methyl-deserpidate,

methyl 18-O-n-butyl-9-methyl-deserpidate,

ethyl 9-methyl-l8-O-methyl-deserpidate,

n-propyl 9-methyl-IS-O-methyl-deserpidate and the like,

lower alkyl 18-O-lower alkyl-IO-methyl-deserpidates,

e.g. methyl lO-methyl-l8-O-rnethyl-deserpidate,

methyl 18-O-ethyll O-methyl-deserpidate,

ethyl IO-methyl-l8-O-methyl-deserpidate and the like,

lower alkyl 18-O-lower alkyl-ll-methyl-deserpidates,

e.g. methyl 1l-methyl-lS-O-methyl-deserpidate,

methyl 1 l-methyl-18-On-propyl-deserpidate,

ethyl ll-methyl- 1 S-O-methyl-deserpidate,

ethyl 18-O-n-butyl-1 l-methyl-deserpidate,

n-propyl 1l-rnethyl-18-O-methyl-deserpidate and the like,

lower alkyl 18-O-lower alkyl-9-methoxy-deserpidates,

e.g. methyl 9-methoxy-18-O-methyl-deserpidate,

methyl 18-O-ethyl-9-methoxy-deserpidate,

methyl Q-methoxy-18-O-n-propyl-deserpidate,

ethyl 9-methoxy-l8-O-methyl-deserpidate and the like,

lower alkoxy 18-O-lower alkyl-l0-methoxy-reserpates,

e.g. methyl lO-methoxy-l8-O-methyl-reserpate,

methyl 18-O-ethyl-10-methoxy-reserpate,

ethyl lO-methoxy-l8-O-methyl-reserpate,

ethyl IO-methoxy-lS-O-n-propyl-reserpate and the like,

lower alkyl 10-ethoxy-18-O-lower alkyl-deserpidates,

e.g. methyl 10-ethoxy-l8-O-methyl-deserpidate,

methyl 10-ethoxy-l8-0-n-propyl-deserpidate,

n-propyl 10-eth0xy-lfi-O-methyl-deserpidate and the like,

lower alkyl 18-O-lower alkyl-12-methoxy-deserpidates,

e.g. methyl 12-methoxy-lS-O-methyl-deserpidate,

methyl 18-O-n-butyl-lZ-methoxy-deserpidate,

ethyl 12-methoxy-1S-O-methyl-deserpidate,

n-propyl 1Z-methoxy-l8-O-rnethyl-deserpidate and the like,

lower alkyl 1l-ethoxy-18-O-lower alkyl-deserpidates,

e.g. methyl ll-ethoxy-lS-O-methyl-deserpidate,

methyl 1 l-ethoxy-l S-O-ethyl-deserpidate,

ethyl 1l-ethoxy-18-O-methyl-deserpidate and the like,

lower alkyl 18-O-lower alkyl-11-n-propyloxy-deserpidates,

e.g. methyl IS-O-methyl-l1-n-propyloxy-deserpidate,

methyl 18-O-n-propyl-1 1-n-propyloxy-deserpidate,

ethyl 18-O-methyl-1 1-n-propyloxy-deserpidate,

ethyl 18-O-methyl-11-n-propyloXy-deserpidate and the like,

lovger alkyl 1l-isopropyloxy-l8-O-lower alkyl-deserpiates,

e.g. methyl 11-isopropyloxy-18-O-methy1-deserpidate,

methyl 18-O-ethyl-l1-isopropyloxy-deserpidate,

ethyl 1 l-isopropyloxy- 1 8-O-methyl-deserpidate,

n-bufityl 1l-isopropyloxy-18-O-methyl-deserpidate and the li e,

lower alkyl 1l-n-butyloxy-l8-O-lower alkyl-deserpidates,

e.g. methyl 1l-n-butyloxy-lS-O-methyl-deserpidate,

methyl 1l-n-butyloxy-l8-O-ethyl-deserpidate,

ethyl 1l-n-butyloxy-lS-O-rnethyl-deserpidate and the like,

lower alkyl 9,l0-dimethoxy-18-O-lower alkyl-reserpates,

e.g. methyl 9,IO-dimethoxy-18-O-methyl-reserpate,

methyl 9, IO-dimethoxy-l 8-O-ethyl-reserpate,

methyl 9, 1 O-dimethoxy- 1 8-O-n-propyl-reserp ate,

ethyl 9,lll-dimethoxy-l8 O-ethyl-reserpate,

n-butyl 9,l-dirneth0xy-l8-O-methyl-reserpate and the like,

lower alkyl l8-O-lower alkyl-l0,1l-methylenedioxydeserpidates,

e.g. methyl l8-O-methyl-l0,l1-methylenedioxy-deserpidate,

methyl l8-O--ethyl-10, 1 l-methylenedioxy-deserpidate,

ethyl lS-O-methyI-IO,l1-methylenedioxy-deserpidate and the like,

lower alkyl -benzyloXy-1 8-O-lower alkyl-deserpidates,

e.g. methyl 10-benzyloxy-l8-O-methyl-deserpidate,

methyl l0-benzyloxy-lS-O-ethyl-deserpidate,

ethyl 10-benzyloxy-IS-O-methyl-deserpidate,

n-propyl IO-benzyloxy-l8 O methyl-deserpidate and the like,

lower alkyl ll-benzyloxY-ltl O-lower alkyl-deserpidates,

e.g. 7 methyl ll-benzyloX -l8-O-methyl-deserpidate,

methyl ll-benzyloxy-l8-O-ethyl=deserpidate,

ethyl ll-benzyloxy lfi-O-methyl-deserpidate and the like,

lower alkyl l8-O-lower alkyl-lO-methylmercapto-deserpidates,

e.g. methyl l8O-methyl-1o-methylmercapto-deserpidate,

methyl l8-O-ethyl-l0-methylmercapto-deserpidate,

methyl lO-methylmercapto-l8-0-n-propyl-deserpidate,

ethyl 1S-O-methyl-lll-methylmercapto-deserpidate, and

the like,

lower alkyl l8-O-lower alkyl-l1;methy1mercapto-deserpidates,

e.g. methyl l8-O-methyl-l l rnethylmercapto-deserpidate,

methyl IS-O-ethyl-l l-methylmercapto-deserpidate,

ethyl l8-O-methyl-l l-methylmercapto-deserpidate,

n-propyl l8-O-methyl-ll-methylmercapto-deserpidate and the like,

lower alkyl 1l-ethylmercapto-l8-O-lower alkyl-deserpidates,

e.g. methyl ll-ethylmercapto-l8-O-methyl-deserpidate,

methyl ll-ethylmercapto-l O-n-propyl-deserpidate,

ethyl l l-ethylmereapto-l 8-O-methyl-deserpidate,

n-propyl ll-ethylmercapto-18-O-methyl-deserpidate and the like,

lower alkyl lO-fluoro-l8-O-lower alkyl-deserpidates,

e.g. methyl ltl-fiuoro-lS-O-methyl-deserpidate,

ethyl IO-fluoro-l8-O-methyl-deserpidate,

ethyl lO-fluoro-lS-O-n-propyl-deserpidate and the like,

lower alkyl ll-fiuoro-l8-O-lower alkyl-deserpidates,

e.g. methyl ll-fiuoro-l8-O-methyl deserpidate,

methyl ll-tluoro-IS-O-ethyl-deserpidate,

ethyl 1l-fluoro-l8-O-methyl-deserpidate and the like,

lower alkyl ltl-chloro-lS-O-lower alkyl-deserpidates,

e.g. methyl lO-chloro-l8-O-methyl-deserpidate,

methyl lO-chloro-l 8-Oethyl-deserpidate,

methyl lO-chloro-l8-O-n-propyl-deserpidate,

ethyl l8-O-n-butyhlO-chloro-deserpidate,

isopropyl l0-chloro-l8-O-methyl-deserpidate and the like,

lower alkyl 9,12-dichloro-l8-O-lower alkyl-deserpidates,

e.g. methyl 9,l2-dichloro-lB-O-i'nethyl-deset idate,

methyl 9,lZ-dichloro-l8-0-n-propyldeserpidate,

ethyl 9,IZ-dichloro-l -o-ethyl-deserpidate and the like,

lower alkyl ll,l2-dichloro-l8-0-lower alkyl=deserpidates,

e.g. methyl 11,12-dichloro-l S-O-methyl-deserpidate,

methyl 1 l,lZ-dichloro-lS-O-ethyl-deserpidate,

ethyl ll,l2-dichloro-l8-0-n-propyl-deserpidate ahd the like,

lower alkyl lG-chloro-lB-O-lower alkyl-reserpates,

e.g. methyl IO-chloro-lS-O-methyl-reserpate,

methyl lO-chloro-lS-O-n-propyl-reserpate,

ethyl l0-chlorol8-O-methyl-resefpate and the like,

lower alkyl l0-bror'no-l8-G-lower alkyl-reserpates,

e.g. methyl lObromo-l8-O-methyl-reserpate,

methyl lO-bromo-l8-O-ethyl-reserpate,

methyl 10-bronio-l8-O-n-butyl-reserpate,

ethyl lO-bromo-l8-O-methyl-1'eserpate,

ethyl l0-bromo-18-O-ethyl reserpate and the like,

lower alkyl 17ix-desmethoxy-l7a-ethoxy-l8-O-lower alkyl-reserpates,

e.g. methyl l7a-desmethoxy-l7a-ethoXy-l8-O-methylmethyl l 7a-desmethoxy l7a ethoxy-IS-O-ethyl-reserpate,

methyl l7a-desmethoxy-l7a-ethoxy-lS-O-mpropylreserpate;

n-propyl l7b desmethoxy-l7a-ethoxy-IS-O-methyl-reserpate and the like;

lower alkyl llbt desmethoxy-l8-O-Iower allcyl-l7a-n-propyloxy-reserpate's, I

eJg. methyl l7a-desmethoxy-l8-O-methyl-l7a-n-propyloxy reserp'at e,

lower alkyl I7a-desinethoxy-17a-isopropyloXy-18-O-lower alkyl-reserpates,

eg. methyl 17a;desmethoxyl7a-isopropyloXy-l8-O- methyl-reserpate,

methyl "l7v deisme'thoxy-lS-O-ethyl-l7a-isopropyloxyreserpate and the like,

lower alkyl l7a-desmethoxy-l7a-eth0Xy-l8-O-lower alkyl deserpidates,

e. g, 7 methyl l7adesmethoxy-lh-ethoxy-18-O methyldeserpidate",

methyl l7cz-desmethoxy-l7zx-ethoxy-l8-0-ethyl-deserpidate,

methyl 17u-desmethoXy 17u-ethoxy-18-O-isobutyl-deserpidate,

ethyl l7ot-desmethoxy-l7a-ethoxy-l8*O-methyl-deserpidate,

ethyl l7a-desmethoxyl7ct=ethoxyl S-O-ethyl-deserpidate and the like,

lower alkyl 17a-cyano-l7a-desmethoxy-18-0-lower alkylreserpates,

e. g. methyl l7a-cyano*l7oz-desmethoXy-lS-D-methylreserpate,

methyl l7a-cyanb-l72x-desmethoXy 1S-O-ethyI-Ieserpate,

methyl l7 x cyan0-l7u-desmethoxy-l8-O-n-propyl-reserpate,

n-propyl l7a-c'y'ano-l7ot-desmethoky-18-O metl1y1-reserpate andthe like,

lower 'alkyl l7oc-cyano-l7a-desmethoxy-l8-0-10Wer alkyldeserpida'tes,

e.g.' methyl 17a-cyaho-l7u-desmethoxy-18-0-methyl- V deserpidate,

methyl 17weyaiib-l7u-desmethoxy-18-0-ethyl-deserpidate,

ethyl Uzi-"cyano-l7b desmethoXy-l8-O-methyl-deserpidate arid the like, 1 I

N,N-di-lower alkyl-arnino-lower alkyl lS-O-loiver alkyl- "re'serpates, in which the N,N-di-lower alkyl-amino group is separated from the carboiryl group by from two to three carbon atoms,

e.g. 2-N,N-dimethylaminoethyl l8-O me'fihyl-reserpate,

2-N,N-dimethylarninoethyl l8-O-eth'yl-reser1pate,

2-N,N-diethylaminoethyl l8 O-methyl-reserpate, 3-N,N-dimethyla minopropyl l8-O-methyl-reserpate and the like,

N,N-di-lower alkyl-amirio-lower alkyl l8-O-lower alkyldeserpidates, in which the N,N-di-lower alkyl-amino group is separated from the carboxyl group by from two to three carbon atoms,

e.g. 2-N,N-dime'thyl'amirioethyl IS-O-methyl-deserpidate,

2-N,N-dimethylaminoethyl l8-O-ethyl-deserpidate,

2-N,N-dimethylarnino-propyl IS-O-methyl-deserpidate and the like,

and pharmacologically acceptable acid addition salts thereof.

' Example 1] To a solution of 1.2 g, of methyl 18-ep i-reserpate in 400 ml. of'methyle e chloride is added 5 ml. ofthe stock fiuoboric acid solution described in Example 1. The reaction mixture is kept at atemperature of about l0' and a solution of an excess of diazobutane in methylene '35 chloride is added. The reaction mixture is worked up as shown in Example 1, and the resulting methyl 18-epi-O- n-butyl-reserpate is obtained, which melts at 224226 (decomposition) The starting material used in the above reaction may be prepared as follows: To a solution of 10.0 g. of methyl reserpate in 70 ml. of pyridine is added 15.8 g. of 4- bromo-benzene sulfonyl chloride; the reaction mixture is allowed to stand 'at room temperature for 2 /2 days and is then poured into ice-water. The organic material is extracted with chloroform, the organic extract is washed with a 5 percent aqueous sodium hydroxide solution and subsequently with water until a neutral reaction is obtained. The organic solution is evaporated to dryness, and the resulting methyl 18-O-(4-bromo-phenylsulfonyl)-reserpate is recrystallized from acetone, M.P. 2092l2; yield: 5.64 g.

A mixture of 6.34 g. of methyl 18-O-(4-bromo-phenylsulfonyl)-reserpate, 100 m1. of water, 300 ml. of p-dioxane and 1.2 g. of N,N,N-triethylamine is heated on the steambath for 41 hours under an atmosphere of nitrogen. The organic solvent is evaporated under reduced pressure, during which operation a precipitate is formed, which is filtered OE and dissolved in methylene chloride. The resulting organic solution is extracted with several portions of 5 percent aqueous hydrochloric acid until the acidic extracts no longer give a precipitate on addition of ammonium hydroxide. The combined precipitates, resulting from the treatment of the acidic extracts with aqueous ammonia, are washed with water and dried to yield 2.73 g. of methyl 18-epi-reserpate monohydrate, M.P. 220-222" (decomposition). Upon drying at 140 under reduced pressure, the above hydrate can be converted into the solvent-free methyl 18-epi-reserpate, M.P. 220-222, [a] =80.5 (in chloroform).

Example 12 A mixture of 1.9 g. of methyl 18-O-(4-bromo-phenylsulfonyl)-reserpate, 0.36 g. of N,N,N-triethylamine and 240 ml. of methanol is sealed in a thick-walled hydrogenation bottle after squirting with nitrogen. The reaction mixture is heated on the steam-bath for 21 hours; the light yellow solution is evaporated, the residue is extracted into methylene chloride, and the organic solution is Washed with a 5 percent aqueous sodium carbonate solution and subsequently with a saturated aqueous sodium chloride solution, and is then dried and evaporated to yield a tan solid, which is muddled with diethyl ether. The latter is dissolved in a 1:2-mixture of benzene and cyclohexane, the solution is passed through charcoal, and the filtrate is evaporated to a small volume, whereupon crystallization occurs. The resulting methyl 18-epi-O-methyl-reserpate of the formula:

melts at 241-244 (with decomposition); yield: 0.86 g. The starting material used in the above procedure may be prepared as shown in Example 11.

Example 13 To a solution of 6.35 g. of methyl l8-epi-O-methyl- V acetone. A gel-like material precipitates immediately, which on scratching becomes crystalline. The mixture is chilled in an ice-bath for thirty minutes, the solid inaterial is filtered off and washed with cold acetone to yield the desired methyl 18-epi-O-methyl-reserpate hydrochloride, M.P. 239242 (decomposition).

Example 14 A solution of 0.4-3 g. of methyl IS-O-methyl-reserpate in 40 ml. of methylene chloride is cooled to 0, and, while stirring, 3 ml. of 0.339 M perbenzoic acid in chloroform is added over a period of seven minutes. The cold, pink solution is stirred for an additional fifteen minutes in an ice-bath, then extracted twice with a cold five percent aqueous sodium carbonate solution and washed with a saturated aqueous sodium chloride solution. The organic layer is separated, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride, and the solution is placed on a column of aluminum oxide (Woelm, neutral, activity 11-111). The column is washed with methylene chloride and the product is eluted with methylene chloride containing one percent of methanol. The solvent is evaporated, and the residue is triturated with acetone to yield 0.11 g. of crystalline material, which is recrystallized by dissolving it in methylene chloride, adding acetone and evaporating most of the methylene chloride. The white, crystalline methyl l8-O-methyl-reserpate N-oxide melts at 238 with decomposition.

Upon treatment of the methyl l8-O-methyl-reserpate N-oxide with hydrochloric acid as shown in Example 6, the desired l8-O-methyl-reserpate N-oxide hydrochloride can be prepared.

The methyl 18-O-ethyl-reserpate N-oxide may be prepared by reacting methyl 18-O-ethyl-reserpate with perbenzoic acid according to the procedure described hereinbefore; the resulting free compound may be converted into the methyl 18-O-ethyl-reserpate N-oxide hydrochloride by treatment with hydrochloric acid in an appropriate solvent, as, for example, described in Example 6.

Example 15 To a solution of 0.8 g. of benzyl reserpate in ml. of methylene chloride is added 20 ml. of the standard fluoboric acid preparation (described in Example 1) and then an excess of diazomethane (using a methylene chloride solution of the reagent). The reaction mixture. is kept at temperatures below l0 and is worked up according to the procedure of Example 1 to yield the desired benzyl 18-O-methyl-reserpate.

The benzyl l8-epi-O-methyl-reserpate may be obtained, for example, by treating benzyl 18-O-(4-bromo-phenylsulfonyl)-reserpate with methanol in the presence of N,N,N-triethylamine according to the procedure described in Example 12.

Example 16 A solution of 2.58 g. of methyl IS-epi-reserpate monohydrate in 700 ml. of methylene chloride is cooled to l0 and 90 ml. of an 0.1 M stock solution of fluoboric acid is added. (The latter is prepared by concentrating commercial 50 percent fluoboric acid to a concentration of about 14 M and diluting the concentrate with the appropriate quantity of an 11:3-mixture of absolute diethyl ether and methylene chloride). The turbid solution is cooled to 12 and ml. of an 0.265 M solution of diazomethane in methylene chloride is added over a period of seven minutes and while stirring. The reaction mixture is stirred for an additional '15 minutes, a small amount of glacial acetic acid is added to destroy the excess of diazomethane, and the solution is then washed twice with 5 percent aqueous sodium carbonate and once with a. saturated aqueous solution of sodium chloride. The organic layer is separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue contains about 20 to 30 percent of the desired Example 17 A mixture of 3.17 g. of methyl IS-O-( t-hromo-phenylsulfonyD-reserpate, 0.6 g. of N,N,N-triethylamine and 240 ml. of absolute ethanol is heated in a sealed vessel on the steam bath for five days while maintaining a nitrogen atmosphere and stirring. The solvent is evaporated under reduced pressure, the residue is dissolved in methylene chloride and the solution is. Washed twice with a five percent aqueous solution of sodium carbonate and once with a saturated aqueous solution of sodium chloride. The organic solution is dried, the solventis evaporated, the residue is triturated with diethyl ether, and the organic solvent is evaporated to leave 2.01 g. of crude methyl 18-epi-G-ethyl-reserpate of the formula:

can

The crude product is recrystallized several times from a mixture of benzene and cyclohexane and melts at 229- 230 (decomposition); [u] =27 (chloroform).

Example 18 A mixture of 5.56 g. of methyl 18-O-(4-oromo-phenylsulfonyD-reserpate, 0.99 g. of N,N,N-triethylamine and 256 ml. of n-propanol is refluxed in a nitrogen atmosphere for 95 hours. After evaporating the-solvent the reaction mixture is Worked up as shown in Example 17 to yield the desired methyl 1S-cpi-O n-propyl-reserpate of the formula:

- sealed vessel at 100 while stirring.

as which melts at 223-225 (decomposition) after recrystallization from a mixture of benzene and cyclohexane; [a] =-26 (chloroform).

Example 20 A total of 0.91 g. of methyl IB-epi-O-n-propyl reserpate is dissolved in 25 ml. of 0.1 N aqueous hydrochloric acid; the solution is frozen and lyophilized to yield the sem'icrystallirie methyl 18-epi O-n propyl-reserpate hydrochloride, which crystallizes as the dihydrate, MP. 213- 223 (decomposition).

Example 21 A mixture of 5.56 g. of methyl 18-O-(4-bromo-phenylsulfonyD-reserpate, 0.9 g. of N,N,N-triethylamine and 24-0 ml. of isopropanol is heated for thirteen days in a The reaction mixture is worked up as shown in Example 17 to yield the methyl 18-epi-O-isopropyl-reserpate, which melts at 225-229 (decomposition) after recrystallization from a mixture of benzene and cyclohexane; ct] =23 (chloroform) The hydrochloride, which is prepared according to the lyophilization procedure of Example 20, crystallizes with 1 /2 moles of water, M.P. 22422 8 (decomposition).

Example 22 i A mixture of 5.56 g. of methyl l8-O-(4-hromo-phenylsulfonyl)-reserpate, 0.9 g. of N,N,N-triethylamine and 333 ml. of n-butanol is refluxed under an atmosphere of nitrogen for 15 /2 hours. The reaction mixture is worked up according to the method described in Example 17 to yield the methyl 18-epi-O-n-butyl-reserpate, which melts at 224226 (decomposition) after recrystallizations from the mixture of benzene and cyclohexane; [a] :l8 (chloroform).

The hydrochloride, Ml. 22 225 (decomposition) is prepared according to the lyophilization procedure described in Example 20 and crystallizes with 1 /2 moles of water.

Example 23 A mixture of 3.17 g. of methyl l8-O-(4-bromo-phenylsulfonyD-reserpate, 0.6 ml. of N,N,N-triethylamine and 10 ml. of benzyl alcohol is heated at 100 for four days while maintaining a nitrogen atmosphere. The benzyl alcohol is evaporated under reduced pressure, the residue is taken up in methylene chloride, which solution is washed with an aqueous solution of sodium carbonate and a saturated solution of sodium chloride, dried and then evaporated. The oily residue is crystallized by stirringwith diethyl ether. The solid material is separated by filtration, is washed with diethyl ether and recrystallized from percent ethanol to yield methyl 18-epi-O- benzyl-reserpate, which melts at 225-226" (decomposition) after recrystallization from a mixture of benzene and cyclohexane; [u] =+12 (chloroform).

Example 24 A mixture of 4.75 g. of methyl l8-O-(4-bromo-phenylsulfonyD-reserpate, 0.9 g. of N,N',N-triethylamine, 50 ml. of ethylene glycol and 5 ml. of p-dioxane (purified by filtration through a column of aluminum oxide, basic, Woelm activity I) is heated at in a nitrogen atmosphere while stirring at for a period of 4 /2 days. The dioxane is evaporated under reduced pressure, and the remaining solution is taken up in methylene chloride. The organic solution is Washed several times with 300 ml. portions of dilute (about 3 percent) aqueous sodium carbonate, with water and with saturated aqueous sodium chloride. On evaporation of the solvents an amorphous residue which crystallizes upon stirring with diethyl ether. The solid material is filtered off, Washed with diethyl ether and recrystallized from acetonitrile to yield the methyl 39 l8-epi-O-(2-hydroxyethyl)-reserpate, M.P. 237239 (decomposition); [Ot] ==26 (chloroform).

The hydrochloride of methyl l8-epi-O-(2-hydroxyethyl)-reserpate, prepared according to the procedure of Example 18, melts at 220226 (decomposition) and crystallizes from the acetone solution as the hemihydrate.

Example 25 A mixture of 4.75 g. of methyl l8-O-(4-bromo-phenylsulfonyl)-reserpate, 0.90 g. of N,N,N-triethylamine and 370 ml. of n-pentanol is refluxed for 24 hours in an atmosphere of nitrogen and then worked up as shown in Example 17. The residue obtained from the methylene chloride solution is triturated with diethyl ether, the solid material is filtered off, and washed with diethyl ether to yield methyl l8-epi-O-n-pentyl-reserpate, M.P. 231-233" (decomposition); [a] (chloroform).

Example 26 0.97 g. of methyl 18-epi-O-n-pentyl-reserpate is dissolved as completely as possible in 100 ml. of 0.1 N aqueous hydrochloric acid, the insoluble material is filtered off, and the solution is freeze-dried to yield methyl l8-epi- O-n-pentyl-reserpate hydrochloride, which melts at 222- 224 (decomposition) and crystallizes with 1 /2 moles of water.

Example 27 A mixture of 4.75 g. of methyl l8-O-(4-bromo-phenylsulfonyD-reserpate, 0.9 g. of N,N,N-triethylamine and 310 ml. of isobutanol is refluxed for four days; the reaction is worked up as shown in Example 17 to yield the methyl 18-epi-O-isobutyl-reserpate, which melts at 234- 236 (decomposition); [a] :l8 (chloroform).

The hydrochloride is prepared according to the lyophilization procedure described in Example and is obtained as the monohydrate, M.P. 2l5224 (decomposition).

Example 28 A mixture of 2.0 g. of methyl IS-O-methylsulfonylreserpate, 0,5 g. of N,N,N-triethylamine and 120 ml. of methanol is placed in a pressure flask, which is then flushed with nitrogen and sealed. The mixture is heated on the steam bath for twenty days; the solvents are evaporated under reduced pressure and the residue is taken up in methylene chloride. The organic solution is washed twice with a five percent aqueous solution of sodium carbonate and once with a saturated aqueous sodium chloride solution, then filtered through a diatomaceous earth preparation and evaporated under reduced pressure. The residue is taken up in ml. of hot benzene, the solution is filtered, the filtrate is clarified with charcoal and diluted with 75 ml. of cyclohexane and then cooled. 1.19 g. of crystalline methyl 18-epi-O-methyl-reserpate, M.P. 230- 233 precipitates and is collected; the product is identical with the compound obtained according to the procedure of Example 12, [uc] =-37 (chloroform).

The starting material may be prepared by adding 2.12 g. of methane sulfonyl chloride and ml. of pyridine to a solution of 6 g. of methyl reserpate in 105 ml. of pyridine while cooling in an ice bath, allowing the mixture to stand at room temperature for three days and diluting it with 750 ml. of a 2.5 percent aqueous sodium hydrogen carbonate solution. The resulting methyl 18- O-methylsulfonyl-reserpate is recrystallized from a mixture of ruetahnol and methylene chloride,'M.P. 244-245 yield: 5.4 g. I 1 i Example 29 A mixture of 0.1 g. of methyl 18-O-(4-nitro-phenylsulfonylyreserpate, 0.02 g. of 'N,N,N-triethylamine and 25 ml. of methanol is heated at 100 in a sealed vessel for 17 /2 hours; the reaction mixture is worked up as shown in Example 17 to yield the methyl 18-epi-O-methyl- '40 reserpate, M.P. 239-241- (decomposition). The product is identical with the compound described according to -the procedure of Example 12.

The starting material is prepared as follows: A mixture of 4.14 g. of methyl reserpate, 5.2 g. of 4-nitro-benzene sulfonyl chloride and 17 ml. of pyridine is allowed to stand at room temperature for three days and is then poured into 200 ml. of ice-water. The aqueous mixture is extracted twice with methylene chloride, the organic extracts are washed with cold aqueous sodium bicarbonate and with saturated aqueous sodium chloride and then evaporated under reduced pressure after drying. The residue is dissolved in methylene chloride, the solution is filtered through a column containing a diatomaceous earth preparation and further elution with methylene chloride yields the crude methyl 18-0-(4-nitro-phenylsulfonyl)-reserpate. The pure compound melts at 202- 204 (decomposition) after recrystallization from acetonitrile.

Example 30 A mixture of 0.64 g. of methyl 18-epi-O-(4-bromophenyl-sulfonyl)-reserpate and 50 ml. of methanol is heated at 100 in a sealed vessel for seven days. The solvent is evaporated, the residue is dissolved as completely as possible in methylene chloride, and the solid material is removed after shaking with a 5 percent aqueous solution of sodium carbonate. The organic solution is washed with saturated aqueous sodium chloride and then evaporated; the residue is taken up in methylene chloride, which solution is passed through a column containing a diatomaceous earth preparation. The column is eluted with methylene chloride and methylene chloride containing 5 percent methanol. The combined eluted product is recrystallized from a mixture of benzene and cyclohexane. The first crystalline crop is discarded, the filtrate is concentrated to yield a small amount of methyl 18-O-methyl-reserpate, M.P. 224-228. The slightly impure product is identical with the compound prepared according to the procedure of Example 1.

The starting material may be prepared as follows: To a solution of 4.32 g. of methyl 18-epi-reserpate in 50 ml. of pyridine is added 6.7 g. of 4-bromo-benzene sulfonyl chloride. After warming to ensure complete solution, the reaction mixture is cooled and allowed to stand for three days and is then poured into ml. of cold Water. The organic material is extracted with methylene chloride, the organic solution is washed with a five percent aqueous solution of sodium carbonate and a saturated sodium chloride solution and evaporated under reduced pressure at a temperature below 50. The residue is washed with acetonitrile to yield the methyl 18-epi-O-(4-bromo-phenyl)- sulfonyl-reserpate, which is purified by recrystallization from acetonitrile, M.P. 2102l2 (decomposition); [a] =-33 (chloroform).

Example 31 minutes under an atmosphere of nitrogen, and then evaporated to dryness under reduced pressure. The oily residue is dissolved in 20 ml. of a 3:2-mixture of acetone and water, the solution is made basic with aqueous ammonia and the organic solvent is evaporated off. 25 ml. of water is added, the organic material is extracted with methylene chloride and the organic solution is dried over sodium sulfate and then evaporated to dryness to leave 0.72 g. of a foamy material.

The residue is chromatographed on 20 g. of alumina (Woelm, neutral, activity II to III). The following fractions are collected and each of the fractions subjected to 

1. PROCESS FOR THE PREPARATION OF A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 